AU2002254265B2 - Imidiazole derivatives and their use as agonists selective at alpha 2B or 2B/2C adrenergic receptors - Google Patents

Description

01-05-'08 12:42 FROM-DCC SYDNEY +61292621080 T-469 P08/13 F-422 00 0 S-1- IMIDIAZOLE DERIVATIVES AND THEIR USE AS AGONISTS SELECTIVE AT ALPHA 2B OR 2B/2C ADRENERGIC RECEPTORS 0 This application derives from International patent application No.

n PCT/US02/08222 filed 13 March 2002 and claims priority from US application C, No. 09/815,362 filed 21 March 2001. This application also claims divisional status to Australian patent application No. 200054749 filed 8 June 2000 and Cl Australian patent application No. 199918025 filed 3 December 1998 which 0 o disclosures are incorporated herein in their entirety.

1. Field of the Invention The present invention is directed to a method of treating pain, particularly chronic pain, glaucoma or elevated intraocular pressure and other diseases with substantially reduced cardiovascular or sedative side effects by administering to mammals inclding humans, cornpounds which are selective agonists of the a2B alone or a2B and a2C adrenergic receptor subtypes and which lack substantial activity at the a2A receptor subtype. The present invention is also directed to novel compounds and pharmaceutical compositions adapted for administering said compounds to inammals, including humans.

2. Brief Description of the Prior Art Compounds which have adrenergic activity are well known in the art, and are described in numerous United States and foreign patents and in scientific publications. It is generally known and accepted in the art that adrenergic activity is useful for treating animals of the marrmmalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having an adrenergic compound or compounds as the active ingredient are useful for treating glaucoma, chronic COMS ID No: ARCS-188850 Received by IP Australia: Time 12:42 Date 2008-05-01 WO 02/076950 PCT/US02/08222 2 pain, nasal congestion, high blood pressure, congestive heart failure and inducing anesthesia.

The two main families of adrenergic receptor are termed alpha adrenergic receptors and beta adrenergic receptors in the art, and each of these two families is known to have subtypes, which are designated by letters of the alphabet, such as a2A, a2B. See the article by Bylund et al, Pharmacol Rev.

46, pp. 121-136(1994). All these and other references cited herein are hereby incorporated within this specification.

SUMMARY OF THE INVENTION It has been discovered in accordance with the present invention that adrenergic compounds which act selectively, and preferably even specifically as agonists of the a2B or a2B a2C (hereinafter referred to as a2B or a2B/2C) receptor subtypes in preference over the a2A receptor subtype, possess desirable therapeutic properties associated with adrenergics but without having one or more undesirable side effects such as changes in blood pressure or sedation. For the purposes of the present invention, a compound is defined to be a specific or at least selective agonist of the a2B or a2B/2C receptor subtype(s) if the compound is at least approximately ten times more potent as an agonist at either the a2B and a2C or both receptor subtypes than at the a2A receptor subtype, or if the difference in the compound's efficacy at the a2B and a2B/2C receptor relative to the a2A receptor is greater than 0.3 and its efficacy at the a2A receptor is 0.4.

Accordingly, the present invention relates to methods of treating animals of the mammalian species, including humans, with a pharmaceutical composition comprising one or more specific or selective a2B or a2B/2C adrenergic agonist compounds as the active ingredient, for treatment of the many diseases or conditions against which alpha adrenergic compounds are useful, including without limitation glaucoma, reducing elevated intraocular 00 pressure, chronic pain, diarrhea, and nasal congestion. In addition, the compounds of this invention are useful for treating muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain IND including neuropathic pain, neurodegenerative diseases including optic neuropathy, spinal ischemia and stroke, memory and cognition deficits, c attention deficit disorder, psychoses including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion.

0o This invention also relates to novel compounds having substantial analgesic activity in the treatment of chronic pain, regardless of origin. Chronic pain may be, without limitation, visceral, inflammatory, referred or neuropathic in origin. Such chronic pain may arise as a result of, or be attendant to, conditions including without limitation: arthritis, (including rheumatoid arthritis), spondylitis, gouty arthritis, osteoarthritis, juvenile arthritis, and autoimmune diseases including, without limitation, lupus erythematosus.

By "chronic pain" is meant pain other than acute pain, such as, without limitation, neuropathic pain, visceral pain (including that brought about by Cron's disease and irritable bowel syndrome and referred pain.

By "acute pain" is meant immediate, usually high threshold, pain brought about by injury such as a cut, crush, bum, or by chemical stimulation such as that experienced upon exposure to capsaicin, the active ingredient in chili peppers.

The present compositions can also be used within the context of the treatment of chronic gastrointestinal inflammations, Crohn's disease, gastritis, irritable bowel disease (IBD) and ulcerative colitis; and in treatment of visceral pain, including pain caused by cancer or attendant to the treatment of cancer as, for example, by chemotherapy or radiation therapy.

P \WPDOCS\Hj Spcs 2\78269053 psdoc-14/04I2008 00

O

S-4- These compositions can be used within the context of the treatment of other chronic pain symptoms, and especially in the treatment of chronic forms of neuropathic pain, in particular, without limitation, neuralgia, herpes, t deafferentation pain, and diabetic neuropathies. In a preferred embodiment 5 these compositions are specifically analgesic in chronic pain models and do not t have significant activity in acute pain models.

O This invention also relates to novel compounds for treating ocular CNI disorders, such as ocular hypertension, glaucoma, hyperemia, conjunctivitis and uveitis.

This invention further relates to novel compounds for treating the pain associated with substance abuse and/or withdrawal.

This invention still further relates to compounds which have good activity when delivered by peroral, parenteral, intranasal, ophthalmic, and/or topical dosing, or injection.

This invention also relates to methods of treating pain through the therapeutic administration of the compounds disclosed herein.

The present invention relates to methods of treating conditions known to be susceptible to treatment through alpha 2 adrenergic receptors.

The present invention also relates to the pharmaceutical compositions used in the above-noted methods of treatment.

The present invention particularly relates to methods for treating diseases and conditions where adrenergic compounds are effective for treatment, but their use is limited because of their generally known side effects.

Thus as an embodiment, the present invention as described is drawn to compounds of the following structure: WO 02/076950 WO 02/76950PCT/US02/08222

~((RA

CH

2

(R

N

H

and

~((RA

N \1 AH--- 1

N

H

in which each x is independently 1 or 2; each R, is independently selected from the group consisting of H; halogen; C1-4 alkyl; C1- alkenyl; C1.4 alkynyl; -COR 4 where R 4 is H, C 1 alkyl or CI-4 alkoxy; C34 cycloalkyl; aryl; heteroaryl; cyano; nitro; trihalornethyl; oxo; or CH 2 )nX-{CH 2 )mr (R4j, where X is 0, S or N, n is 0-3, m is 0-3, o is 0-1, and R.5 is methyl or -2 each R 2 and each R3 are independently selected from the group consisting of H; halogen; C34 alkyl; C14 alkenyl; Cj- alkynyl; COR 4 where R4 is H; CI-4 alkyl or Calkoxy; C 3 .6 cycloalkyl; aryl; heteroaryl; cyano; nitro; trihalomethyl; oxo; or (Hj

X-{CH

2 )m{R 5 )O where X is 0, S or N, n is 0-3, m is 0-3, o is 0-1, and R.

5 is methyl or

HI-

2 or an R.

2 and an R.

3 together condense to form a saturated, partly saturated, or unsaturated ring structure having the formula 4C(R6)p)q-X-(C(R6)p), -Xr-4C(R 6 where each R-6 is independently selected from the group consisting of H; halogen; C14 alkyl; C 1 .4 alkenYl; Cj.4 alkynyl; -COR4 where R4 is H, Cj.4 alkyl or C14 alkoxy; C3-6 P:\WPDOCS\ljwSpccs 2\78269053 pgs doc-14/04/2008 00 -6cycloalkyl; aryl; heteroaryl; cyano; nitro; trihalomethyl and oxo where each p is Sindependently 1 or 2, q is 0-5, r is 0-5, u is 0-5; each X is independently O, S, or N and s is 0 or 1; provided that q r u s t is less than 6; n Y is selected from the group consisting of O; S; N; -(C(R 7 )z)s-where each R 7 is independently as previously defined for Rl, each z is independently 1-2, and s is 1-3; CH=; -CH=CH-; or YICH 2 -where YI is O, N, or S; and the dotted lines are optional double bonds, with the proviso that if the ring including Y is a cyclohexane ring or a heterocyclic 5 member ring said ring is not fully unsaturated, and that ifY is O, N or S, the ring including Y contains at least one said double bond, said compound further having selective agonist activity at the c2B or d2B/cd2C adrenergic receptor subtype(s) over the 2A adrenergic receptor subtype, and all pharmacologically acceptable salts, esters, stereoisomers and racemic mixtures thereof.

The invention subject of this application is set out in the claims that follow. These and other aspects and embodiments of the invention are as described below.

DETAILED DESCRIPTION OF THE INVENTION Compounds which are used in the pharmaceutical compositions and methods of treatment of the present invention are selective or specific agonists of the o2B or o2B/2C adrenergic receptor subtypes, in preference over the 2A receptor subtype. In accordance with the present invention, a compound is considered a selective o2B or a2B/2C agonist if that compound's difference in efficacy as an agonist of the o2B or o2B/2C receptor subtype(s) compared to the o2A receptor subtype is greater than 0.3 and its efficacy at the a2A receptor subtype is <0.4 and/or it is at least approximately 10 times more potent.

Preferably, the compounds utilized in accordance with the present invention are specific agonists of the a2B or o2B/2C receptor subtypes. Specifically, in this regard, a specific agonist is defined in the sense that a specific a adrenergic agonist does not act as an agonist of the o2A receptor subtype to any measurable or biologically significant extent.

A set of agents has been discovered that are functionally selective for the a2B or o2B/2C subtypes of said adrenergic receptors. This preferential WO 02/076950 PCT/US02/08222 7 activity can be determined in a variety of functional assays such as Cyclic AMP Production, Shimizu et al, J. Neurochem. 16, pp. 1609-1619 (1969); R-SAT (Receptor Selection and Amplification Technology), Messier et al, Pharmacol.

Toxicol. 76, pp. 308-311(1995) and the Cytosensor microphysiometer, Neve et al, J. Biol. Chem. 267, pp. 25748-25753, (1992) using cells that naturally express individual subtypes or have had one of the subtypes introduced. The cells or recombinant receptors used should be human or from a species that has been shown to have a similar pharmacology. In the study below, the RSAT assay on cells that have been transiently transfected with the human a2A (cl0 gene), rat a2B (RNG gene) and human a2C (c4 gene) receptors was used. The rat a2B receptor has been shown to have a pharmacology that corresponds to the human a2B receptor (see, for example, Bylund et al., Pharmocol, Rev. 46, pp. 127-129(1994)).

In the treatment of glaucoma, particularly, topical administration may be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like maybe applied to the eye in glaucoma and dermally to treat other indications. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.

Applicants have discovered that the compounds of this invention activate a 2 receptors, particularly o2B receptors. In a particular use, these compounds act as a highly effective analgesic, particularly in chronic pain models, with minimal undesirable side effects, such as sedation and cardiovascular depression, commonly seen with agonists of the a 2 receptors.

In the treatment of pain such compounds may be administered at pharmaceutically effective dosages. Such dosages are normally the minimum dose necessary to achieve the desired therapeutic effect; in the treatment of chromic pain, this amount would be roughly that necessary to reduce the WO 02/076950 PCT/US02/08222 8 discomfort caused by the pain to tolerable levels. Generally, such doses will be in the range 1-1000 mg/day; more preferably in the range 10 to 500 mg/day.

However, the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the pain, the age and weight of the patient, the patient's general physical condition, the cause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal; particularly a human being. Preferably, the patient will be given the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like. However, other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, intrathecal, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.

If the drug is to be administered systemically, it maybe confected as a powder, pill, tablet or the like or as a syrup or elixir for oral administra-tion.

For intravenous, intraperitoneal, intrathecal or epidural administra-tion, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository or as an extended release formulation, including the dermal patch form, for deposit on or under the skin or for intramuscular injection.

Treatment of glaucoma or any other indications known or discovered to be susceptible to treatment by adrenergic compounds will be effected by administration of therapeutically effective dose of one or more compounds in accordance with the instant invention. A therapeutic concentration will be that WO 02/076950 PCT/US02/08222 9 concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation. However, it is anticipated that in the treatment of, for example, glaucoma, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 3% will usually constitute a therapeutically effective concentration. If administered systemically, an amount between 0.001 and 50 mg per kg, preferably between 0.001 and 10 mg per kg body weight per day, but most preferably about 0.01 to 1.0 mg/kg, will effect a therapeutic result in most instances.

Because the a2B and a2B/2C specific selective agonist compounds lack substantial 2A side effects, treatments of diseases or conditions with such compounds in accordance with the present invention is advantageous, particularly when the treatment is directed to a human having cardiovascular problems.

The general structures of exemplary specific a2B and a2C agonist or selective a2B and a2B/2C agonist adrenergic compounds which are used in the pharmaceutical compositions and methods of treatment of the present invention are provided by general Formulas, below.

In one aspect of the invention, a compound having selective agonist activity at the a2B or a2B/2C adrenergic receptor subtype(s) as compared to the 2A adrenergic receptor subtype is represented by the general formula WO 02/076950 PCT/US02/08222 R 3 x (R2( R N Y

H

I

wherein the dotted lines represent optional bonds provided that two double bonds may not share a common carbon atom; R is H or lower alkyl; X is S or

C(H)R

1 wherein R' is H or lower alkyl, but R 1 is absent when the bond between X and the ring represented by

Y

is a double bond; Y is O, N, S, (CR' 2 wherein y is an integer of from 1 to 3, CH=CH- or -Y'CH 2 wherein Y' is O, N or S; x is an integer of 1 or 2, wherein x is 1 when R 2

R

3 or R 4 is bound to an unsaturated carbon atom and x is 2 when

R

2

R

3 or R 4 is bonded to a saturated carbon atom; R 2 is H, halogen, hydroxy, lower alkyl, alkoxy, alkenyl, acyl, alkynyl, or, when attached to a saturated carbon atom, Rz maybe oxo; R 3 and R 4 are, each, H, halogen, lower alkyl, alkenyl, acyl, alkynyl, aryl, e.g. phenyl or naphthyl, heteroaryl, e.g. furyl, thienyl, or pyridyl, and substituted aryl or heteroaryl, wherein said substituent may be halogen, lower alkyl, alkoxy, alkenyl, acyl, alkynyl, nitro, cyano, trifluoromethyl, hydroxy, etc. or, together, are Y' (C(R 2 )x)y -(C(R 2

Y'-(C(R

2

(C(R

2 yl 1 2 and Y 1

-(C(R

2

Y'-(C(R

2 wherein z is an integer of from 3 to 5, z' is an integer of from 2 to 4 and x and y are as defined above, and further either end of each of these divalent moieties may attach at either R3 or R4 to form a condensed ring structure shown generally as WO 02/076950 PCT/US02/08222 11 (R2)x 2R

R

Y

and the rings formed may be totally unsaturated, partially unsaturated, or totally saturated provided that a ring carbon has no more than 4 valences, nitrogen no more than three and 0 and S have no more than two.

In another aspect of the invention in the above compound is represented by the formula (R3)x (R2 x (R(4) RN

Y

H n wherein X may be C(H)R 1 and R 1 is H.

In said compound of formula II, R 2 may be H and

Y

may represent a furanyl radical.

In such furanyl derivatives of Formula II, R 3 and R 4 together may be (CH)4 or R 3 may be H and R 4 may be t-butyl, or R 3 and R 4 may be H, or R 3 may be H and R 4 may be methyl or ethyl.

Alternatively, in the compound of Formula I, R 1 may be methyl and y WO 02/076950 PCT/US02/08222 12 may represent a furanyl radical.

Alternatively, in said compounds of Formula II, R 2 may be H and may represent a thienyl radical.

In such thienyl derivatives of Formula II, R 3 and R 4 together, may represent (CH 2 4 or R 3 may be phenyl and R 4 may be H, or R 3 and R 4 together, may represent (CH 2 3 S, or R 3 and R 4 may be H, or R 3 and R 4 together, may represent (CH) 4 or may be R 3 may be H and R 4 may be methyl, or R 3 may be bromo and R 4 may be H, or R 3 may be hydrogen and R 4 may be chloro, or R 3 may be methyl and R 4 may be hydrogen.

Alternatively, in the compounds of Formula II

Y

may represent a cyclohexyl radical.

In such cyclohexyl derivatives of Formula II, R 2 may be hydrogen and

R

3 and R 4 may, together, represent (CH) 4 or R 2 may be oxo and R 3 and R 4 together, may be (CH) 4 or R 2 may be hydrogen or oxo and R 3 and R 4 together, may represent (CH) 2 S, or R 2 may be hydrogen and R 3 and R 4 may, together, represent (CH 2 4 forming an octahydronaphthalene, or R may be oxo and R 3 and R 4 may, together, represent (CHz) 4 or R 2 may be oxo and R 3 and R 4 together, may represent (CH) 2

C(CH

3 or R 2 may be hydrogen and R 3 and

R

4 together, may represent S(CH 2 2 or R 2

,R

3 and R 4 may be H, orR 2 may be oxo and R 3 and R 4 together, may represent (CH) 2

C(OCH

3 )CH, or R 3 and R 4 together may represent -Y-C(R2)x-C(R2)x- Y'-wherein Y' is N, forming a tetrahydroquinoxaline wherein R 2 may be hydrogen or oxo.

Alternatively, in the compounds of Formula II WO 02/076950 PCT/US02/08222 13

Y

may represent a tetrahydroquinoline radical wherein R 3 and R 4 together are C(R2)x-C(R 2 )x-C(R2)x- wherein Y 1 is N. In such tetrahydroquinoline derivatives (R2)x may be hydrogen or oxo; or may represent a tetrahydro-isoquinoline radical wherein R 3 and R 4 together are -C(R2)x-Y 1 -C(2)x-C(R2)x- wherein Y' is N and (R 2 )x may be hydrogen or oxo.

Alternatively, in the compounds of Formula II

Y

may represent a cyclopentyl radical.

In such cyclopentyl derivatives of Formula II, R 2 may be H and R 3 and

R

4 together, may represent (CH) 4 or R Z maybe oxo and R 3 and R 4 together, may represent (CH)4, or R 2 may be hydrogen and R 3 and R 4 together, may represent (CH 2 3 In another aspect of the invention, Y is (CH 2 3 and X maybe CH and R may be oxo or X may be CH2 and R may be H and R 3 and R 4 together, may represent (CH) 4 Alternatively,

R

3 and R 4 together, may represent (CH) 4

Y

may be CH 2 C(CR 2)2 wherein R' is hydrogen, or Y may be -CH2C(Me)- and R 2 maybe hydrogen or oxo.

Finally, in the compounds of Formula II

Y

WO 02/076950 WO 02/76950PCT/US02/08222 14 may represent a phenyl radical.

in such phenyl derivatives of Formula 1, X may be CH 2 R maybe H or

CH

3 R W~ and R 4 may be H, or R3 and R 4 together, represent O(CR 2 2 0 to provide a I ,4-benzodioxan derivative, or alternatively, X may be S and W2 ,W and R 4 may beH.

In another aspect of the invention, said compound has the formula R2

I

wherein Y is S or 0.

In such compound of Formula III, X may be C(H)R1, P, R 1 W3, W2 and RWmaybe HandYmaybeoorS.

In another aspect of the invention, said compound has the formula IN R R~ (R 4 x and W2 and R 4 together, represent (CR) 4 WO 02/076950 PCT/US02/08222 P3 al.

In such compounds of Formula IV, Y' may be O, R 2 may be oxo and X is CH or CH2 or one of R 2 is hydroxy and the other may be H, or R 2 may be

H.

In such compounds of Formula IV, Y' may be S, X may be CH 2 and R may be oxo, or m a ymay be H and maybe ay be CH and R 2 may be oxo.

In another aspect of the invention, the compound having selective activity at the 2B or 2B and 2C adrenergic receptor subtype(s) as compared to the 2A adrenergic receptor subtype is represented by the formula

W

z

N-

N:

V

alternatively W is a bicyclic radical selected from the group consisting of

R

R6,- WO 02/076950 PCT/US02/08222 16 wherein R 5

R

6

R

7 and R 8 are selected from the group consisting of H and lower alkyl provided that at least one of R and R 6 or R 6 and R 7 are OC(R 9

)C(R

9 to form a condensed ring with wherein R 9 is H, lower alkyl or oxo; and wherein R' 1 is H, lower alkyl, phenyl or lower alkyl substituted phenyl, and Z is O or NH. Compounds wherein W is norbomyl are disclosed and claimed in commonly assigned co-pending application 09/003902, filed on 7 January, 1998, which is hereby incorporated by reference in its entirety.

In one aspect of the invention Z may be O and W may be 2fH and R 1 0 may be selected from the group consisting of H, phenyl and omethylphenyl, e.g. R' 0 may be o-methylphenyl.

In another aspect of the invention W may be WO 02/076950 PCT/US02/08222 17

R

(R )xC 9 I1 (R )xC N

R

wherein Z may be NR, R may be methyl or hydrogen, one of (R 9 )x may be H and R 5 may be H.

Alternatively, W maybe

N

R R 8 wherein R may be H and R 8 may be methyl.

It is understood that wherein a reference to lower alkyl, alkoxy, alkenyl or alkynyl is made above, it is intended to mean radicals having from one to eight carbons, preferably from one to four carbon atoms. Where reference to aryl is made above, it is intended to mean radicals of from six to fourteen carbon atoms, preferably from six to ten carbon atoms. Where reference is made to halogen, fluoro and chloro are preferred.

The invention is further illustrated by the following examples (including general synthetic schemes therefore) which are illustrative of various aspects of the invention and are not intended as limiting the scope of the invention as defined by the appended claims.

WO 02/076950 WO 02/76950PCT/US02/08222 Example A Synthesis of 1-dimethylsulfamoy1-2-t-butyldimethylsilyl-5imidazolecarboxaldehyde: CN CIS 2 NMe2 CN 1) n-BuLi, -78'C H Et 3 N, benzene %ONe 2) TBDMSCI 1. 2 Nj BM 1) sec-BuLl, NOHC

N

SO

2 NMe 2 2)DFSO 2 NMe 2 3 4 Procedure Imnidazole 0.29 moi), triethylamine (41.OmL, 0.29 mol) and NN-dhmethylsulfamoyl chloride (31 .6mL, 0.29 mol) were added to 320mL of benzene. The reaction was stirred for 48h at room temperature (it) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product niniHg, 115*- 118'C) afforded 38.7g of a clear and colorless oil. Upon cooling the product solidifies to give white crystals 1-(Dimethylsulfaloyl) imidazole (18.8g, 0.11 mol) was added to 430ml, of tetrahydrofuran The solution was cooled to -780 C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dxopwise to the reaction flask. Upon completion, the WO 02/076950 PCT/US02/08222 19 reaction was stirred for Ih at -78°C. t-Butyldimethylsilylchloride (17.8g, 0.12 mol) in 50mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography ethyl acetate/ hexane as eluant) afforded a light yellow solid.

Recrystallization from pentane gave 30g of white crystals l-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (5.0g, 17.3 mmol) was added to 100mL of THF. The solution was cooled to -20 0

C.

A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for lh at -20 0 C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/ hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5imidazolecarboxaldehyde Example B-1 Procedure for Preparation of 4(5)-(7-methoxy-1,2,3,4tetrahydronaphthalen-2-ylmethyl)-lH-imidazole, hydrogen chloride salt: WO 02/076950 PCT/US02/08222

PA'

0

CH

3 0 fN

TBDMS

O HC~ N

SO

2 NMe 2 40% H SO 4

H

2 (40 psi) Pd/C ethanol

OH

NaBH 4 methanol Et 3 SiH, CF 3

CO

2

H

CH

2 C1 2

CH

3 0 N

H

HCI C 3

HCI

H

Procedure 7-Methoxy-1-tetralone (1.5g, 8.5 mmol) and Idimethylsfamoyl-2-t-butyldimethylsilyl-5- iniidazolecarboxaldehyde (2.7g, 8.5 mimol) were added to 8.5 mL of a 40% solution of sulfuric acid. The reaction was heated for 24h at 901C. After cooling to rt, the reaction was made- basic with excess concentrated amimorium hydroxide. The rmixture was extracted twice with THF. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to afford 2.7g of a yellow solid comprising 3-(3H-imidazole-4(5)ylmrethylefle)- 7 WO 02/076950 PCT/US02/08222 21 imelULUy L.i'oman-4-one. The crude product was suspended in 100mL of ethanol and a palladium on carbon catalyst 0.27g) added. The mixture was shaken in a Parr hydrogenator apparatus while under psi of hydrogen. After 19h the reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure. Column chromatography with 7% methanol in chloroform afforded 1.05g (46%) of a tan color solid comprising 2-[3H-Imidazole-4(5)-ylmethyl]-7methoxy-3,4-dihydro-2H-naphthalen-l-one (0.5g, 1.95 mmol) was added to 20mL of methanol. Sodium borohydride (74mg, 1.95 mmol) was added to the solution. After stirring for 2.5h at rt the reaction mixture was quenched with water. The reaction mixture was then extracted twice with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was separated and dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to afford 0.5g of a white solid comprising 2-[3H-Imidazole-4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2Hnaphthalen-1-ol. The crude product was dissolved in 26mL of dichloromethane. Triethylsilane (2.5mL, 15.6 mmol) and trifluoroacetic acid (4.8mL, 62.3 mmol) were added and the reaction stirred at rt for 22h. The reaction was made basic with 2N NaOH and the organic layer separated and washed with brine. The solution was dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography with 7% methanol in chloroform afforded 0.

3 9g of a tan color oil The product was dissolved in methanol and an excess of hydrogen chloride (HC1) in ether was added. The solution was concentrated under reduced pressure to yield 0.3g of a tan color solid. Column chromatography with WO 02/076950 WO 02/76950PCT/US02/08222 22 7% methanol in chloroform afforded 0.

25 g of 4(5)-(7-methoxy- 1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole, hydrogen chloride salt as white crystals after recrystallization from a midxture of acetone and methanol.

'H NMR (300 MHz, CD3OD) 8.83 1H), 7.38 1H), 6.95 1H, 6.66 1H, J=8.4Hz), 6.57 1H1), 3.73 311), 2.71-2.81 (in, 51-1), 2.43-2.52 (in, 1H), 1.90-2.14 (in, 211), 1.40-1.51 (in, 1H).

Following the procedure of Example B-i various fused ring comhpounds are reacted to yield the imidazole derivatives listed below.

Example B-2(a-d) 4-chromanone (2a) 3-(3H-iniida2zol-4(5)ylinethylene)chroman-4-one (2b) 3-(3H-imidazol-4(5)-ylinethyl)chroman-4-one (2c) 3-(3H-inmidazol-4(5)-ylinethyl)chroman- 4-ol (2d) 4(5)-chroman-3-ylinethyl-111-im-idazole Example B-3(a-b) 1-tetralone (3a) 2-(3H-imiddazol-4(5)-ylinethyl)-3,4dihydro-2H-naphthalen-1-one (3b) 4(5)-(1,2,3,4-tetrahydronaphthalen-2ylmethyl)-lH-iniidazole WO 02/076950 WO 02/76950PCT/US02/08222 23 Example B-4(a-b) 4-methyl-l-tetralone (4a) 4(5)-(4-methyl-1,2,3,4tetrahydronaphthialen-2vlmnethyl)-1H-imidazole dihydro-2H--naphthalen-1-one Example Thiochromnan (5a) 3-(31--imidazol-4(5)yhriethylene)thiochroman-4-one 3-(3H-imidazol-4(5)ylmethyl)thiochroman-4-one Example B-6 The hydrogen chloride salt of the previous compound is prepared by step 5 of the method of Example B-1, above.

Thiochroman 4(5)-thiochroman-3-ylmethyl-1in-ddazole Example B-7(a-c) I-indanone (7a) 2-(3H-imidazol-4(5)yhmethylene)indan- 1-one (7b) 2-(3H-imidazole-4(5)-ylmefiyl)indan-1-one (7c) 4(5)-indan-2-'ylmethyl-lH-imidazole WO 02/076950 WO 02/76950PCT/US02/08222 24 Example B-8(a-b) 7-methyl-l-tetralone (8a) 2-(3H-i-mdazol-4(5)-ylmethyl)-7methyl- 3,4-dihydro-2H-naphthalen-1one (8b) 4(5)-(7-methyl-1,2,3,4tetrahydronaphthalen-2-ylmethyl)-lHimidazole The hydrogen chloride salt of this compound is prepared by the method of Example B-6.

Example B-9(a-c) 4-keto-4,5,6,7-tetrahydrothianaphthene (9a) 4(5)-(4,5,6,7-tetrahydroylmethyl)-lH-irndazole The hydrogen chloride salt of this compound is prepared by the method of Example B-6.

(9b) 5-(31H-imiddazol-4(5)ylmethyl)-6,7-dihydro-5Hbenzo~bthiophen-4-one The hydrogen cloride salt of this compound is prepared by the method of Example B-6.

(9c) ylmethyl)-lH-imidazole Example 4,4-Dimethyl-l-tetralone 4(5)-(4,4-dimnethyl-1,2,3,4tetrahydronaphffhalen- 2 yhnethyl)-1H-imidazole WO 02/076950 WO 02/76950PCT/US02/08222 Example B-11(a-b) 1-Benzosuberone (Ila) 4(5)-(6,7,8,9-terhYdrO-5Hbenzocydloheptell-6-ylmfethyl)-lHin-idazole 6,7,8,9-tetrahydrobenzocyclohepten- Example C-1 Procedure for Preparation of 4(5)-thiophefl-3-yhmethyllH-flidazole:

N

SONMe 2 1) n-BuiU 2) TBSCI 3) n-BuUi 4) r OH SO 2 NMe 2

N

I-TBS

s

N

TBAF

OH SO 2 NMe 2

N

C$

N

Et3SiH S02NM821.5 N HCI

H

6 WO 02/076950 PCT/US02/08222 26 Procedure 1-(Dimethylsulfamoyl)imidazole 2 .0g, 11.4 mmol) is taken up in 42mL of anhydrous THF and cooled to -78 0 C. n-BuLi (6.6mL, 10.6 mmol) is added dropwise to the solution of The resultant solution is stirred at -78°C for 30 min. Tert-butyldimethylsilylchloride

(TBSCI)

(1.

6 g, 10.6 mmol) in 8mL of THF is added to the reaction. The reaction is warmed to rt and stirred overnight. The next day the reaction is cooled to -20 0 C and 7.3mL (11.6 mmol) of n- BuLi added. After stirring at -20 0

C

for 45 min, 3-thiophene carboxaldehyde (1.OmL, 11.6 mmol) is added to the reaction mixture. Then reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with water and diluted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (2:5 ethyl acetate/ hexane) affords 3.0g (7.5 mmol) of 2-(tbutyldimethylsilyl)-5-(hydroxythiophen-2-ylmethyl)imidazole-1sulfonic acid dimethylamide (1.5g, 3.74 mmol) is taken up in 37mL of THF. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (4.1mL, 4.1 mmol) is added dropwise to the solution of The reaction is stirred overnight at rt. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. 0.

9 4g (3.3 mmol) of 5-(hydroxythiophen-2-ylmethyl)imidazole- 1-sulfonic acid dimethylamide is recovered. (0.5g, 1.74 mmol) is taken up in 23mL of dichloromethane, to the solution is added 2.2 mL (13.9 mmol) of triethylsilane and 4.3 mL (55.7 mmol) of trifluoroacetic acid. The reaction is stirred at rt overnight and then quenched with WO 02/076950 PCT/US02/08222 27 water and neutralized with solid sodium bicarbonate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using a 1:1 mixture of ethyl acetate and hexane affords 0.42g (1.55 mmol) of 5-(thiophen-2-ylmethyl)imidazole-l-sulfonic acid dimethylamide (0.4 2 g, 1.55 mmol) is taken up in of a 1.5N HC1 solution and heated at reflux for 3h and then stirred at rt overnight. The reaction is diluted with ethyl acetate, neutralized with solid sodium bicarbonate and then made basic with 2N NaOH. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using a 10:1 mixture of chloroform and methanol affords 0.17g (1.0 mmol) of 4(5)-thiophen-3ylmethyl-1H-imidazole 1 H NMR (300 MHz, CDaOD) 7.52 1H), 7.25-7.27 1H), 6.96-7.01 (m, 2H), 6.77 1H), 3.98 2H).

Example C-2 The 2-carboxaldehyde isomer of 3-thiophene carboxaldehyde is substituted into the method of Example C-1 to yield 4(5)-thiophen-2ylmethyl-lH-imidazole Example C-3 5-Methyl-2-thiophene carboxaldehyde of 3-thiophene carboxaldehyde is substituted into the method of Example C-1 to yield methylthiophen-2-ylmethyl)-lH-imidazole WO 02/076950 WO 02/76950PCT/US02/08222 28 Example C-4 5-Chloro-2-thiophene carboxaldehyde of 3-thidophene carboxaldehyde is substituted into the method of Example C-i to yield clilorothiophen-2-ylrmethyl)-lH-ilhidazole Example 2-Furan carboxaldehyde is substituted into the method of Example C-1 to yield 4 (5)-furan-2-yhnethyl-1H-inidazole Example C-6 3-Furan carboxaldehyde is substituted into the method of Example C-i to yield 4(5)-f uran- 3-yhmethyl-H-inidazole Example C-7 5-Methyl-2-furan carboxaldehyde is substituted into the method of Example C-1 to yield 4(5)-(5-methylfuran-2-yhlethyl)-iH-imiddazole Example C-8 Benzaldehyde is substituted into the method of Example C-i to yield 4(5)-benzyl-1H-im-idazole Example C-9 2-Thianaplithene carboxaldehyde is substituted into the method of Example C-i to yield 4(5)-benzob]thiophel-2-yTmethyl-iH-ilidazole Example 2-Benzof uran carboxaldehyde is substituted into the method of Example C-i to yield 4(5)-benzofuran-2-yhnethyl-iH-imfidazole WO 02/076950 WO 02/76950PCT/US02/08222 29 Example C-il 5-Ethyl-2-furan carboxaldehyde is substituted into the method of Example C-1 to yield 4(5)-(5-ethylfaran-2-yhlethyl-H-intflidazole Example C-12 4-Bromo-2-thiopherte carboxaldehyde is substituted into the method of Example C-1 to yield 4(5)-(4-bromothiophen-2-ylmethy1)-1H-ilidazole Example C-13 4-Phenyl-2-tiophene carboxaldehyde is substituted into the method of Example C-1 to yield 4(5)-(4-phenyltbiophen-2-yhflethyl)-iH-imnidazole Example C-14 4-Methyl-2-thiophene carboxaldehyde is substituted into the method of Example C-i to yield 4(5)-(4-methylthiophen-2-yhlethyl)-lHin-ddazole,hydrochloride salt WO 02/076950 WO 02/76950PCT/US02/08222 E~xample D-1 Procedure for Preparation of oxazolklin-2-ylidene-(3-phenyl bicyclo[2.2.11hept-2-yl) amidne: 0 CH 3

NO

2 /IKOH /MeO H OH HOI H

C

6

H

5 N0 2

C

6 H(7zN02 6 Hs H 2 Pd-C 1) 0 H chloroisocynate CICHCHC NO 2

NH

2 2) NaHCO 3

~~C

6

H

HN

N

Procedure The endo exo relative stereochemistry of the compound was prepared, by making the f-ritrostyrene as shown above. Treatment of a methanol solution of benzaldehyde (10g, 94.3 mmole) with nitromethane 943 nmnol) in the presence of sodium hydroxide (3N in methanol to pH=8) afforded the nitro alcohol in 60% yield. Dehydration of the alcohol was effected by treatment with methanesulfonyl chloride (3.5 6 g& 31.1mmole) followed by triethylamidne (6.3g, 62.2 mmol) in dichloromethane (35m1L) to give 97% yield of product. Kugelrohr distillation was done to purify compound. Construction of the bicyclo[2.2.l1heptane skeleton was carried out in one step. The Diels- Alder reaction was conducted by warm-ing the nitrostyrene (4.5g, 30.2 mmole) with cyclopentadiene (3.98g, 60.4 mmole) in 1, 2-dichioroethane WO 02/076950 WO 02/76950PCT/US02/08222 31 (l0nil). The Diels-Alder reaction proceeds in approximately a 3:1 endo:exo nitro ratio. Both the ratio and relative stereochemidstry was demonstrated through x-ray analysis. Reduction of both the nitro group and the'olefin was carried out under an atmosphere of hydrogen in the presence of 10% by weight palladium on charcoal. Separation of isomers was conveniently carried out at this stage using flash chromatography with 5% ammonia-saturated methanol in dichioromethane. The amine (0.7g, 3.74 rnmole) was treated first with cliloroethylisocyanate (0.38ni1, 4.49mmole) to afford the chloroethylurea, which was then warmed in the presence of aqueous NaI-C03 solution to afford oxazolidin-2ylidene-(3-phenyl bicyclo[2.2.1I hept-2-yl) amine in 51 yield.

1 H NMR (300 I-k, CDC13) d 1.36-1.80 (in, 61H), 2.14 1H-, J=4.4OHz), 2.37 111), 2.65 1H), 3.71-3.78 (in, 3.95-3.98 (in, 11-1), 4.19-4.25 (t, 2H-, J=17.15Hz, J=8.36Hz), 7.17-7.29 (in, SH).

Example D-2 Oxazolidin-2-ylidene-(3-o-tolyl bicyclo[2.2.1]hept-2-yl)amnine is prepared by substituting o-methyl 1-nitrostyrene in the method of D-1 Example D-3 Bicyclo[2.2.l]hept-2-yl oxazolidin-2-ylidene amine is prepared by substituting nitroethene in the method of D-lI WO 02/076950 WO 02/76950PCT/US02/08222 32 Example E-1 Procedure for Preparation of imiddazolidin-2-ylidene-(4-methyl-3,4dihydro-2H-benzo[1,4Joxazin-6-yl)an-ine: 0 2 N NH 2 aOH

H

0 2 N N 0 2 Me 0 2 N

N

4 0 Et N/IDMA

CA~

2 C1 2 20 C 0 2 N NH

-COH

reflux BH,3-SMe 2 THF /reflux /24h Pd-C I H 2 THE MeOH (1:1) 0 2 N

N

3 Me H2N N 1) HCHO NaBH 3

CN

2) AcOH HN rN S0 3

H

2C t3 Me H

N

6 Procedure To 2-amino-4-riitrophenol (4.00g, 25.95 nimol), triethylamidne (15.2OmL, 109.0 numol) and 4-dimethylaminopyridine (0.063g, 0.52 nunol) slurried in anhydrous CH 2 C1 2 (250mnL) at 0 0 C under argon added WO 02/076950 PCT/US02/08222 33 chloroacetyl chloride (2.27 mL, 28.55mmol) via syringe. After refluxing for 72h pure product was filtered off and washed with water. The mother liquor was washed successively with phosphoric acid saturated sodium bicarbonate, water and brine and then dried over MgSO 4 This solution was adhered to silica and purified by flash chromatography on silica with hexane/ethyl acetate to give additional product. The combined solids were dried in vacuo to give pure 6-nitrq-4H-benzo[1,4]oxazin- 3 -one (4.12g) in 82% yield. To a slurry of (1.49g, 7.65 mmol) in anhydrous THF (40mL) under argon in a 2-neck round-bottom flask equipped with a reflux condenser was added borane-dimethyl sulfide complex (15.3mL, 30.62 mmol). The mixture was heated at reflux until starting material was no longer observed via thin layer chromatography The reaction mixture was cooled to rt and carefully quenched by the dropwise addition of methanol. The resulting mixture was then refluxed an additional minutes. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography on silica with hexane/ethyl acetate to give pure 6-nitro-3,4-dihydro-2H-benzo[1, 4 ]oxazine (136g) as an orange solid in 99% yield. To (0.032g, 0.178mmol) and formalin (37% in H20, 0.20 mL, 2.67 mmol) in anhydrous acetonitrile (1.5mL) at ambient temperature was added sodium cyanoborohydride (0.034g, 0.534 mmol). This solution was stirred for 30 min before adding glacial acetic acid (0.032mL, 0.534 mmol). The resulting mixture was stirred an additional 16h. The organics were taken up in diethyl ether and washed successively with NaOH (2N) and brine, dried over MgSO 4 and concentrated in vacuo. The resulting solids were purified by flash chromatography on silica with hexane/ethyl acetate to give pure 4-methyl-6-nitro-3,4-dihydro-2H-benzol,4]oxazine (4) WO 02/076950 PCT/US02/08222 34 (0.031g) in 93% yield. To (2.16g, 11.12 mmol) and 10% palladium on carbon (0.21 6 g, 10 wt. under argon was added methanol (MeOH) followed by THF (30mL). Hydrogen was bubbled thru the resulting slurry until no remained visible by thin layer chromatography Celite was added and the mixture was filtered through a bed of celite followed by a MeOH wash. The resulting solution was concentrated in vacuo to give pure 4-methyl-3,4-dihydro- 2H-benzo[1,4]oxazin-6-ylamine (1.86g) as a pale purple oil in 100% yield which was carried on without further purification. To (1.86g, 11.34 mmol) and imidazoline-2-sulfonic acid (1.84g, 12.24 mmol) in anhydrous acetonitrile (50mL) under argon at 0°C was added triethylamine (3.26mL, 23.36 mmol). This solution was gradually warmed to ambient temperature and stirred for 16h. At that time an additional amount of imidazoline-2-sulfonic acid (0.86g, 5.55 mmol) was added and the resulting mixture was stirred an additional 5h. This solution was concentrated in vacuo and the residues were taken up in The organics were extracted into CH 2 C1 2 and washed twice with NaOH and then brine, dried over MgSO 4 and concentrated in vacuo.

The resulting foam was purified by flash chromatography on silica with 20% methanol (saturated with ammonia) in chloroform to give pure imidazolidin-2-ylidene-(4-mehyl-3,4-dihydro-2H-benzo[1,4]oxazin-6yl)amine (0.905g) in 34% yield.

1H NMR (CDC13): 2.81 3H); 3.26 J=8.9 Hz, 2H); 3.60 4H); 4.26 2H); 4.60 (vbrs, 2H); 6.34 (dd, J=8.2 Hz, J=2.4 Hz, 1H); 6.39 J=2.4 Hz, 1H); 6.68 J= 8.2 Hz, 1H).

WO 02/076950 WO 02/76950PCT/US02/08222 Example F G Procedure for Preparation of 6-(im-idazolidifl-2-ylidefle methyl-4H-benzojl,4]oxazin-3-ofle and methyl-3,4-dihydro2Hbenzo11,4]oxazinh.8-yl)an-hdfe

NH

2 1) TEAI/DMAP!1CH2

C

2 OH 2) c-yC 1 0 c'o 2 0 2 N NO 3

NO

2 4

H

2 N cINI Pd-C 1 H 2 TrHF-MeOH (1:1) Et 3 N (2.5 eq.) CH3CN refiux 80h N 'Y NH S0 3

H

(3.6 eq.) H e N -N I) HN0 3

/H

2 S0 4 0

C

2) H 2 01 ice

H

2 N N0

NH

2 6 HN NH "f H N NO 7 4H

NH

2 6 Et 3 N (2.5 eq.)

CH

3 CN I reflux 80h N..y NH

SOH

(3.6 eq.) 1) BH 3 -Me 2

S

2) HCI HC eI WO 02/076950 PCT/US02/08222 36 Procedure To 2-amino-3-methylphenol (14.72g, 0.120 mol), triethylamine (35.0mL, 0.251 mol) and 4-dimethylaminopyridine (0.

2 9g, 2.39 mmol) in anhydrous CH 2 C1 2 (100mL) at 0°C under argon was added chloroacetyl chloride (10.0mL, 0.126 mol) dropwise via syringe. After the addition was complete the resulting solution was refluxed for 24h. The organics were washed successively with phosphoric acid saturated sodium bicarbonate, water and brine and then dried over MgSO 4 The resulting solution was concentrated and taken up in THF to which ether was added. The resulting crystals were filtered off to give pure methyl-4H-benzoll,4]oxazin-3-one (12.

3 0g) in 63% yield. To (2) (14.64g, 89.72 mmol) dissolved in concentrated H2SO 4 (65 mL) at -10 0

C

was added 70% concentrated HNO 3 (8.08g, 89.72 mmol) in concentrated

H

2

SO

4 (25mL) with rapid mechanical stirring at a rate whereby the internal temperature was maintained below -5 0 C. As soon as the addition was complete the mixture was poured onto crushed ice (500mL) and the resultant solids were filtered off and slurried in cold water (300 mL) while sufficient NaOH was added to adjust the pH to 7.

The recovered yellow powder was dissolved in THF, adhered to silica and purified by flash chromatography with 60% hexane and ethyl acetate to give the nitrated product as a mixture of two regioisomers, i.e.

the desired 6-substituted aromatic comprising 6-nitro-5-methyl-4Hbenzo[1,4]oxazin-3-one and the 8-substituted by-product comprising 8-nitro-5-methyl-4H-benzo[1,4]oxazin-3-one These isomers are separated with difficulty at this point and were carried on to the next step as a mixture. To a mixture of (1.93 g, 9.27mmol) and (0.48g, 232 mmol) dissolved in a solution of MeOH WO 02/076950 WO 02/76950PCT/US02/08222 37 (300mL) and TI-F (300mL) under argon was added 10% palladium on carbon (1.20g). The resulting solution was subjected to H2 at one atmosphere pressure. After 16h the catalyst was filtered off and the resulting solution was concentrated in vacuo and purified by flash chromatography on silica with 50% hexane and ethyl acetate to give 6amino-5-methyl-4H--benzo[1,4]oxazin-3-one (0.96 g) in 46% yield and 8-amiino-5-methyl-4H-benzo[1,4loxazin-3-one (0.17 g) in 8% yield. (1.20g, 6.74 mmol), imidazoline-2-sulfonic acid (2.02g, 13.48 mmol) and triethylamine (2.35mL, 16.85 mmol) were heated at reflux in anhydrous acetonitrile (5OmL) under argon for 48h. At that time an additional amount of in-idazoline-2-sulfonic acid (1.01g, 6.74 mmol) and triethylamine (1.4lmL, 10.12 mmol) were added and the resulting mixture was stirred an additional 24h. This solution was concentrated in vacuo and the residues were taken up in a solution of CHCl 3 isopropyl alcohol and washed successively with NaOH (1N) and brine, dried over MgSO 4 and concentrated in vacuo. The resulting foam was purified by flash chromatography on silica with methanol saturated with ammonia in chloroform to give 6- (imidazolidin-2-ylidenean-iino)-5-methyl-4H-benzo[1,4]oxazin-3-one (7) (0.42g) as a 'foam in 27% yield along with 55% recovered starting material. The HCI salt was recrystallized from a mixture of ethanol and diethyl ether (EtOH/Et 2 O) to give fine white needles.

1 H NMR (DMSO): 2.10 3.59 4H) 4.53 M1); 6.83 J=8.6 Hz, 6.90 J= 8.6 Hz, 1H); 8.07 (brs, 2H); 10.15 (vbrs, 1H); 10.42 (s, 11-).

WO 02/076950 PCT/US02/08222 38 (0.222 g, 1.35mmol), imidazoline-2-sulfonic acid (0.223 g, 1.49mmol) and triethylamine (0.415 mL, 2.98mmol) were heated at 95 0 C in anhydrous acetonitrile (10 mL) in a sealed tube for 2h. At that time an additional amount of imidazoline-2-sulfonic acid (0.112 g, 0.75mmol) was added and the reaction was continued for an additional 16 h. This solution was concentrated in vacuo and the residues were taken up in a solution of CHC1 3 /isopropyl alcohol and washed successively with NaOH (2N) and brine, dried (MgSO 4 and concentrated in vacuo. The resulting oil was recrystalizied from CHCl 3 to give pure 6-(imidazolidin- 2-ylideneamino)-5-methyl-4H-benzo[l,4]oxazin- 3 -one (0.048 g) as a white powder in 15% yield along with 35% recovered starting material. To a slurry of (0.08 g, 0.321mmol) in anhydrous THF mL) under argon in a 3-neck round-bottom flask equipped with reflux condenser was added borane-dimethyl sulfide complex (0.48 mL, 0.936mmol). The mixture was heated at reflux until starting material was no longer observed via thin layer chromatography (3 The reaction mixture was cooled to room temp-erature and carefully quenched by the dropwise addition of methanol. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography on silica using 20% methanol saturated with ammonia/ chloroform to give imidazolidin-2-ylidene-(5-methyl-3, 4 dihydro-2H-benzo[1,4]oxazin-8-yl)amine (0.03 g) as the HC1 salt in 37% yield.

11 NMR (CDC13): 2.07 3H); 3.46 J=4.3Hz, 2H); 3.55 4H); 4.24 (t, J=4.3Hz, 2H); 5.60 to 5.95 (vbrs, 2H); 6.44 J=8.0 Hz, 1H); 6.57 Hz, 1H).

WO 02/076950 PCT/US02/08222 39 Example H Procedure for Preparation of 4 5 )-phenylsulfanyl-1H-imidazole

SO

2 NMe 2 N S

N

S S i T B S T B S

SO

2 NMe 2

SO

2 NMe 2

N

TBAF S N aq. HCI N

H

2 3 Procedure 1-(N,N-dimethylsulfamoyl)imidazole (1.5g, 8.6 mmol) was taken up in 28mL of THF. The solution was cooled to -78oC and n-BuLi (5.4mL, 8.6 mmol) added dropwise via syringe. After stirring at -780C for 1h TBSCI (1.3g, 8.56 mmol) in 10mL of THF was added. The bath was removed and the reaction allowed to warm-up to rt. The reaction mixture was stirred overnight. The reaction mixture was cooled to and n-BuLi (5.4 mL, 8.6 mmol) added. After 45 min phenyldisulfide (1.9g, 8.6 mmol) in 8mL of THF was added. The reaction mixture was stirred at rt for 48h. The reaction mixture was quenched with saturated anmunonium chloride and extracted with ethyl acetate. The organic layer was collected and washed with water and then brine. The solution was dried over sodium sulfate and the solvent removed under reduced WO 02/076950 PCT/US02/08222 pressure. Flash chromatography EtOAc/hexane) afforded 2.8g mmol) of sulfonic acid dimethylamide as a yellow color oil. The compound (1) (2.8g, 7.0 mmol) was dissolved in THF and the solution cooled to 0°C.

TBAF (7.0mL, 7.0 mmol) was added dropwise to the solution. The reaction mixture was stirred overnight at rt. The next day the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure.

Flash chromatography (50% EtOAc/hexane) afforded 474mg of phenylsulfanylimidazole-l-sulfonic acid dimethylamide and 290mg of 5-phenylsulfanyl-lH-imidazole The 478mg of was added to 2N HC1 and the solution heated at reflux for 2h. The reaction mixture was made basic with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (EtOAc) afforded as a white crystalline solid. A combined total of 360mg (2.0 mmol) of is recovered.

1H NMR (300 MHz, CDsOD) 7.91 1H), 7.37 1H), 7.19-7.23 2H-), 7.07-7.11 3H).

WO 02/076950 WO 02/76950PCT/US02/08222 41 Example I Procedure for Preparation of 4(5)-(1,2,3,4-tetraliydronaphthalert-2methane sulfonic acid salt: 0 HO 3 V cO1

B

3 -M9 2

S

THF I20 0

C

2 4 1) Ph?3 I imlidezole 2) 1 2 l1benzene 1) mCPBA CH 2

CI

2 2) KF filter 0 MgBr ~78 to 250C NaN 3 1 acetone-H- 2

C

24h I 70 0

C

CQ4NH

N

3 O H Ph&P /DEAD JTHIF 20 C/4h

H

2

NNH

2

-H

2 0 EtOH I refiux 24h N-3"

N

H2 Pd-C I H 2 /1I atm EtOAc

IH

2

N

N H 2 (EtO) 3 CH IMeSO 3

H

105 0 H H MeSO 3 11 Procedure To 1,2,3,4-tetrahydronaphthalen- 2 -carboxylic acid (4.93g, 27.42 nimol in anhydrous TI-F (250mL) at 20'C under argon was added 3.26 mL (32.90 nimol) borane-dimethysulfide (BH-L-Me2S) via syringe.

WO 02/076950 PCT/US02/08222 42 After stirring for 16h MeOH (4mL) was added and the mixture was warmed to 55°C until no more gas was evolved. The mixture was concentrated to an oil, taken up in EtO and washed successively with 2M phosphoric acid, saturated sodium bicarbonate, water and brine and then dried over MgSO 4 and reconcentrated. The resulting oil was purified by high vacuum Kugelrohr at 150 0 C to give pure alcohol (1,2,3,4-tetrahydronaphthalen-2-yl)methanol (4.09g) in 93% yield. To triphenylphosphine (10.179g, 38.809 mmol) and imidazole (2.

6 4g, 38.809 mmol) in anhydrous benzene (175mL) was added the iodine (8.60g, 33.865 mmol) in benzene (75mL) with rapid stirring followed by in benzene (50mL). After 3h the solids were filtered off and the filtrate was reduced in vacuo to a volume of 50mL to which was added hexane (200mL). The resultant solids were filtered off and the filtrate was washed successively with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica with hexane to give pure 2-iodomethyl-1,2,3,4tetrahydronaphthalene (6.239g) in 90% yield. To (10.02 g, 36.85 mmol) and Cul (1.41g, 7.37 mmol) in anhydrous THF (50mL) at -78 0

C

under argon was added vinylmagnesium bromide (1M in THF, 73.70mL, 73.70 mmol) slowly at a speed at which no color developed. This solution was allowed to warm to 0°C and stirred for 6h. The resulting mixture was recooled to -40 0 C and quenched by the careful addition of 2M phosphoric acid (35mL). This solution was diluted with 100mL water and extracted with hexanes. The organic fractions were washed successively with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica with hexane to give 2-allyl-1,23,4-tetrahydronaphthalene (4) WO 02/076950 PCT/US02/08222 43 (5.61 8 g) in 88% yield. (5.61 5 g, 32.645 mmol) and metachloroperbenzoic acid (m-CPBA) (14.08g, 81.613 mmol) were stirred in anhydrous methylene chloride (50mL) for 16h. The solids were filtered off and potassium flouride KF (5.11g, 88.142 mmol) was added and this mixture was stirred an additional hour. The solids were filtered off and the reaction was concentrated in vacuo. The resulting oil was purified by flash chromatography on silica with 5% ethyl acetate in hexane to give 2- (1,2,3,4-tetrahydronaphthalen-2-ylmethyl)oxirane 5 .41g) in 88% yield. To (1.626g, 8.649 mmol) in a solution of acetone (20mL) and water (5mL) was added sodium azide (1.97g, 30.271 mmol). This solution was warmed to 85 0 C and stirred for 48h. The solution was concentrated in vacuo and the residues were taken up in CHC1 3 and washed successively with water and brine, dried over MgSO 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica with 30% ethyl acetate in hexane to give pure 1-azido-3-(1,2,3,4-tetrahydronaphthalen-2-yl)propan- 2 -ol (1.76 2 g) in 88% yield. A mixture of (1.

88 g, 8.140 mmol), triphenylphosphine (2.67g, 10.173 mmol), phthalimide (1.50g, 10.173 mmol), diethyl azodicarboxylate (DEAD) (1.77g, 10.173 mmol) were stirred in anhydrous THF (50mL) for 4h. This solution was concentrated in vacuo, taken up in a solution of hexane (25mL) and ether (25mL) and stirred for 16h. The solids were filtered off and the filtrate was concentrated in vacuo. The resulting oil was purified by flash chromatography on silica with 20% ethyl acetate in hexane to give 2-[1-azidomethyl-2-(1,2,3,4tetrahydronaphthalen-2-yl)ethyl]isoindole-1, 3 -dione (2.487g) contaminated with a small amount of impurity which was carried on without further purification. A mixture of (3.93g, 10.917 mmol) and hydrazine (0.680mL, 21.833 mmol) were heated in ethanol (60mL) at WO 02/076950 PCT/US02/08222 44 reflux for 16h. The solids were filtered off and the filtrate was concentrated in vacuo. The residues were purified by flash chromatography on silica with 5% MeOH in CH 2 Clz to give 1azidomethyl-2-(1,23,4-tetrahydronaphthalen-2-yl)ethylamine (8) (2.057g) in 88% yield. A mixture of (2.056g, 8.940 mmol) and palladium on carbon (0.260 g) were stirred in MeOH (30mL) under 1 atmosphere of hydrogen for 16h. The solids were filtered off and the filtrate was concentrated in vacuo. The residues were purified by flash chromatography on silica with 10% ammonia saturated MeOH in CHC1 2 to give 3 2 3 ,4-tetrahydro-naphthalen-2-yl)propane-l,2-dione (1.557g) in 85% yield. A mixture of (0.590g, 2.892 mmol) and methanesulfonic acid (0.980mL, 14.460 mmol) were heated in triethylorthoformate (10mL) at 105 0 C 3h. The reaction was concentrated in vacuo and the solids were filtered off. Subsequent recrystalization of these solids from a mixture of MeOH and ether gave pure tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-lH-imidazole, methane sulfonic acid salt (0.435g) in 48% yield.

1H NMR (CDC1 3 1.37 to 1.56 1H); 1.56 to 1.70 1H); 1.80 to 2.02 2H); 2.32 to 2.55 2H); 2.72 3H); 2.75 to 2.95 3H); 3.48 to 3.59 1H); 3.93 to 4.08 1H); 4.31 to 4.47 1H); 7.00 to 7.20 4H); 8.46 1H); 10.04 1H); 10.35 (brs, 1H).

WO 02/076950 PCT/US02/08222 Example J-1 Procedure for Preparation of 4(5)-cyclohexylmethyl-H-imidazole NSOzNMe 2

TBAF

N TBS 1) n-BuLi N -'BS N' TBS -/>-TBS

SO

2 NMe 2 1 2) 32 N 2

SO

2 NMe 2

H

N

HCI

N reflux

N

4 Procedure 2-Tert-butyldimethylsilyl-l-dimethylsulfamoy imidazole (1) (4.1g, 14.2 mmol) is taken up in 47 mL of anhydrous THF and cooled to 0 C. n-BuLi (8.9 mL, 14.2 mmol) is added dropwise to the solution of The resultant solution is stirred at -20°C for 45 min.

Cyclohexylmethyl iodide (3.14g, 14 mmol) is then added dropwise to the reaction mixture. Then reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with water. The mixture is extracted with ethyl acetate (3 x 100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/ hexane) affords 2.2 6 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-l-dimethylsulfamoyl imidazole (2.26g, 5.6 mmol) is taken up in 56 mL of THF and cooled to o0C. A 1M solution of TBAF in THF (5.6 mL, 5.6 mmol) is WO 02/076950 PCT/US02/08222 46 added dropwise to the solution of The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:1 ethyl acetate/ hexane) affords 1.2g (4.42 mmol) of -1-dimethylsulfamoyl imidazole (1.2g, 4.42 mmol) is taken up in 25 mL of a 1.5N HC1 solution and heated at reflux for 2h. The reaction is cool to rt and diluted with ethyl acetate. The mixture is brought to pH 13 with 2N NaOH and then extracted with chloroform (4 x 100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (9:1 chloroform/ methanol) affords 700 mg (4.27 mmol) of 4(5)-cyclohexylmethyl-1H-imidazole 1H NMR (CDC 3 0.92 to 1.0 2H); 1.16 to 1.26 3H); 1.57 to 1.73 6H); 2.48 J=6.9 Hz, 2H); 6.77 1H); 7.56 1H) Example J-2 (S)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substituted into the method of Example J-1 to yield (S)-4(5)-(1,2,3,4-tetrahydronaphthalen-2ylmethyl)-1H-imidazole. (S)-2-iodomethyl-1,2,3,4tetrahydronaphthalene was prepared from (S)-1,2,3,4-tetrahydro-2naphthoic acid. (S)-1,2,3,4-tetrahydro-2-naphthoic acid was prepared from the resolution of 1,2,3,4-tetrahydro-2-naphthoic acid Med. Chem.

1983,26,328-334) WO 02/076950 WO 02/76950PCT/US02/08222 47 Example J-3 (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substituted into the method of Example J-1 to yield (R)-4(5)-(1,2,3,4-tetrahydronaphthalen-2ylmrethyl)-IH-imiddazole. (R)-2-iodomethyl-1,2,3,4tetrahydronaphthalene was prepared from (R)-1,2,3,4-tetrahydro-2naphthoic acid. (R)-12,3,4-tetrahydro-2-naphthoic acid was prepared from the resolution of 1,2,3,4-tetrahydro-2-naphthoic acid UJ. Med. Chiem.

1983, 26, 328-334) t0 Example K-i Procedure for Preparation of 4(5)-(4,5,6,7-tetrahydrobenzo[blthiophen-2ylmethyl)-1H-imidazole:

OQ)S

1 1) n-BuLi 2)

N

I~ \>-TBDMS OHCf

N

SO

2 NMe 2

N

I SO 2 N Me 2 3

TBAF

N

OHSO

2 N Me 2 C S' O EtSiH

CI

3 C0 2

H

CH

2

CI

2 I S0 2 NMe 2

S

1) 1.5N HOI reflux 2) HOI

HCI

K NH

SQ

WO 02/076950 PCT/US02/08222 48 Procedure 4,5,6,7-tetrahydrobenzo[b]thiophene 2 .1g, 15 mmol) is taken up in 75mL of anhydrous THF and cooled to -78°C. n-BuLi (6.0mL, mmol) is added dropwise to the solution of The resultant solution is stirred at -78 0 C for 60 min. 1-Dimethylsulfamoyl-2-t-butyldimethylsilylimidazolecarboxaldehyde (4.8g, 15 mmol) in 25mL of THF is added to the reaction. The reaction is warmed to rt and stirred for 2h before being quenched with water and diluted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:3 ethyl acetate/ hexane) affords 5.

2 g (11 mmol) of 2-(tert-butyldimethylsilyl)-5-[hydroxy-(4,5,6,7tetrahydrobenzo[b]thiophen-2-yl)methyl]imidazole-1-sulfonic acid dimethylamide (5.2g, 11.3 mmol) is taken up in 57mL of THF. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.3mL, 11.3 mmol) is added dropwise to the solution of The reaction is stirred for lh 15min reaction before being quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Recrystallization from hexane/ ethyl acetate affords 5-[hydroxy-(4,5,6,7tetrahydrobenzo[b]thiophen-2-yl)methyl]imidazole-l-sulfonic acid dimethylamide (2.1g, 6.2 mmol). An additional 2g of the crude product is also recovered. (2.0g, 5.9 mmol) is taken up in 78mL of dichloromethane, to the solution is added 7.5 mL (46.9 mmol) of triethylsilane and 14.4 mL (0.19 mol) of trifluoroacetic acid. The reaction is stirred at rt overnight and then quenched with water and neutralized with 2N NaOH. The organic layer is washed with water followed by WO 02/076950 WO 02/76950PCT/US02/08222 49 brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using a 1:1 mixture of ethyl acetate and hexane affords 0.

7 5g (2.3 mmol) of (4,5,6,7-tetrahydrobenzobthiophel-2-ylmethyl)in-idazole--sulforic acid dimethylamide (0.42g, 1.55 nimol) is taken up in l5mL of a HCl solution and heated at reflux for 2h and then stirred at rt overnight. The reaction is diluted with ethyl acetate, neutralized with 2N NaOH. The organic layer is washed with water followed by brine.

The organic phase is dried ove r sodium sulfate and the solvent removed under reduced pressure. The crude product is dissolved in methanol and an excess of HC in ether is added. Solvent is removed under reduced pressure to afford O.6g (2.3 nimol) of tetrahydrobenzoib]thiophen-2-ylmethyl)-H-imidazole 1H NMR (CD3OD): 8.80 1q-I; 7.34 1H); 6.57 4.18 2H-); 2.65 to 2.69 (in, 2.51 to 2.55 (mn, 2H); 1.74 to 1.83 (in, 4H) Example KC-2 2-(Tert-butyl) furan is substituted into the method of Example K-I to yield (5-tert-butylfuran-2-yhnethyl)-H-imidazole Example K-3 5,6-Dihydro-41--thienoI2,3-bI~tbopyrafl is substituted into the method of Example K-i to yield 4(5)-(5,6-dihydro-4H-thieno[2,3-blthiopyrafl-2ylmethyl)-lH-imidazole WO 02/076950 WO 02/76950PCT/US02/08222 Example L Procedure for Preparation of 4(5)-(1-furan-2-ylethyl)-1H-im-idazole: 1) n-BuLi 2) 2N CHO T

TB.Y

-TB 2- B S0 2 N Me 2 OH SO 2 NMe 2 o N OH SO 2 NMe 2 4 O N HO SONMe 2 Mn0 2 0 N 0 S0 2 NMe 2 MeMgCI Et 3 SiH CF C 2

H

0 N S0 2 NMe 2 1.5 NHCI reflux 0 N

*H

8 Procedure 2-(Tert-butyldimethylsily)-1-(dimTethylsulfamoyl)iuidazole (1) (3.3 g, 11.4 nimol) is taken up in 38niL of anhydrous TI-IF arnd cooled to 78TC. n-BuLi (7.2mL, 11.4 nimol) is added dropwise to the solution of The resultant solution is stirred at -78o(C for 30 mn. 2-Furfural (2) WO 02/076950 PCT/US02/08222 51 (0.94mL, 11.4 mmol) is added to the reaction. The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/ hexane) affords 4.4g (11.4 mmol) of 2-(t-butyldimethylsilyl)-5-(furan-2ylhydroxy-methyl)imidazole-l-sulfonic acid dimethylamide (3) (4.4g, 11.4 mmol) is taken up in 110mL of THF and cool to 0° C. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.4mL, 11.4 mmol) is added dropwise to the solution of The reaction is stirred overnight at rt. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. 3.9g of crude (furan-2-ylhydroxymethyl)imidazole-l-sulfonic acid dimethylamide (4) is recovered. (1.0g, 3.7 mmol) is taken up in 37mL of dichloromethane, to the solution is added 1.6g (18.5 mmol) of manganese dioxide. The reaction is stirred at rt overnight and then filtered through celite. The eluent is collected and the solvent removed under reduced pressure. Flash chromatography using a 1:1 mixture of ethyl acetate and hexane affords 0.69g (2.6 mmol) of 5-(furan-2ylcarbonyl)imidazole-l-sulfonic acid dimethylamide (0.69g, 2.6 mmol) is taken up in 26mL of THF. The solution is cool to -780 C. 1.7mL (5.1 mmol) of a 3M solution of methylmagnesium chloride is added.

After stirring at -780 C for 1.5h reaction is warmed to rt and stirred for an additional hour. The reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water WO 02/076950 PCT/US02/08222 52 followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Crystallization from ether/hexane affords 0.39g (1.4 mmol) of 5-(1-furan-2-yl-1hydroxyethyl)imidazole-l-sulfonic acid dimethylamide An additional 0.19g of is recovered. (0.58g, 2.0 mmol) is taken up in 27mL of dichloromethane, to the solution is added 2.6 mL (16.3 mmol) of triethylsilane and 5.5 mL (71.4 mmol) of trifluoroacetic acid. The reaction is stirred at rt overnight and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure.

Flash chromatography using a 2:1 mixture of ethyl acetate and hexane affords 0.53g (2.0 mmol) of 5-(1-furan-2-ylethyl)imidazole-l-sulfonic acid dimethylamide (0.34g, 1.3 mmol) is taken up in 10mL of a HC1 solution and heated at reflux for 30min and then stirred at rt overnight. The reaction is diluted with ethyl acetate and then made basic with 2N NaOH. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (10:1 chloroform/methanol) affords O.lg (0.62 mmol) of 4(5)-(1-furan-2ylethyl)-lH-imidazole 1 H NMR (300 MHz, CDCIs) 7.56 1H), 7.33-7.34 1H), 6.81 1H), 6.29-6.31 6.06-6.07 4.22 J= 7.2 Hz, 1H), 1.63 J= 7.2 Hz,3H).

WO 02/076950 PCT/US02/08222 53 Example M Procedure for Preparation of 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6ylmethyl)-4-methyl-lH-imidazole:

-N

SO

2 NMe 2

I

1) n-BuL 2) TBDMSCI- 3) n-BuLi 4) OHC 0 OH

SO

2 NMe, O N TBAF q j>-TBS (On

N

3 OH p02NM e 2 CO ,1 CN Et 3 SiH CF CO 2

H

RHCI,

SO

2 NMe 2

N

1.5 N HC1 reflux (ZO2N (0 N >II Procedure 4-Methyl--(dimethylsulfamoyl)imidazole (2.0g, 10.6 mmol) is taken up in 42mL of anhydrous THE and cooled to -78 0 C. n-BuLi (6.6mL, 10.6 mmcl) is added dropwise to the solution of The resultant solution is stirred at -78 0 C for 30 mmn. Tert-butyldimethylsilyichioride (TBSC1) (1.6g, 10.6 mmol) in 10mL of THF is added to the reaction. The reaction is warmed to rt and stirred overnight. The next day the reaction is cooled to -20 0 C and 7.3mL (11.6 nimol) of n- BuLi added. After stirring at -20'C for 30 min, 1,4-benzodioxan-6-carboxaldehyde (1.

92 g, 11.7 WO 02/076950 PCT/US02/08222 54 mmol) in 10mL of THF is added to the reaction mixture. Then reaction is warmed to rt and stirred for 3h. The reaction is quenched with water and diluted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:2 ethyl acetate/ hexane) affords 3.9g (8.4 mmol) of 2-(tbutyldimethylsilyl)-5-[(2,3-dihydro benzo[1,4]dioxin-6-yl)hydroxymethyl]-4-methylimidazole-l-sulfonic acid dimethylamide (1.0g, 2.14 mmol) is taken up in 21mL of THF. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (2.35mL, 2.35 mmol) is added dropwise to the solution of The reaction is stirred for 30min at rt. The reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using ethyl acetate as eluant affords 0.75g (2.12 mmol) 5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4methylimidazole-1-sulfonic acid dimethylamide (0.7 5 g, 2.12 mmol) is taken up in 28mL of dichloromethane, to the solution is added 2.7mL (17.0 mmol) of triethylsilane and 5.2mL (67.8 mmol) of trifluoroacetic acid. The reaction is stirred at rt overnight and then quenched with water and neutralized with solid sodium bicarbonate.

The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using a 3:1 mixture of ethyl acetate and hexane affords 0.

63 g (1.87 mmol) of 5-(2,3dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methylimidazole-l-sulfonic acid dimethylamide (0.

63 g, 1.87 mmol) is taken up in 10mL of a WO 02/076950 PCT/US02/08222 HCJ solution and heated at reflux for. The reaction is diluted with ethyl acetate, neutralized with solid sodium bicarbonate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure.

Crystallization from ether/hexane affords 0.33g (1.43 mmol) of dihydrobenzo1,4]dioxin-6-ylmethy1)-4-methy-1H-irmidazole 1H NMR (300 MHz, acetone-d 6 7.37 1H), 6.66-6.67 3H), 4.18 (s, 4H), 3.73 2.13 3H) Example N Procedure for Preparation of 2-(3H-inidazol4(5)-ylmethyl)-3,4,5,6,7,8hexahydro-2H-naphthalen-1-one 4(5)-(2,3,4,4a,5,6,7,8octahydronaphthlen-2-ylmethyl)-H-inidazole and (1,2,3,4,5,6,7,8-octahydronaphthalen-2-ylmethyl)-1H-imidazole 0 OHC N i) NaOH/EtOH N ,>reflux ccN

N

H 2) 40 H 2 S0 4

H

reflux

N-I

H

2

NNH

2 NaCH, refiux diethylene glycol N HCI

N

N

'N

H

H

70N-3 N-2 WO 02/076950 PCT/US02/08222 56 Procedure: 1-Decalone (10.0g, 66 mmol) and 4(5)-imidazole carboxaldehyde (6.3g, 66 mmol) were added to 100 mL of ethanol. To the solution was added NaOH (5.2g, 130 mmol) in 20 mL of water. The reaction was heated at reflux for 5 days. The reaction was cooled to rt and made basic with aqueous HC1. The solution was extracted with THF/ethyl acetate.

The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure to afford the crude product. The crude product was heated at reflux in 40% H 2 S04 for 1 day. The reaction was cooled to rt and made basic with saturated K 2 COs. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure. Purification by flash chromatography (15:1 CHaC/MeOH) afforded N-1 (4.9g, 32% yield).

1H NMR: 7.55 6.77 1H), 3.08-3.14 1.52-2.46 13H).

The free base of the hydrochloride salt of N-1 (3.0g, 11 mmol) was generated with NaOH and then added to diethylene glycol (100mL). To the solution was added hydrazine hydrate (3.2 mL, 100 mmol) and the reaction was left to stir overnight at rt. NaOH (3.1g, 77 mmol) was added and the solution heated at reflux for 5 days. The reaction was cooled to rt and diluted with water. The solution was extracted with THF/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure. Purification by flash chromatography (8:1 CHsC/MeOH) afforded N-2 (0.64g, 27% yield).

1H NMR: 7.58 6.76 1H), 5.24 J= 4.3 Hz, 1H), 0.91-2.58 (m, 16H).

WO 02/076950 WO 02/76950PCT/US02/08222 57 N-2 (1.0g, 4.6 mmol) was added to 10 mL of concentrated HCl The solution was stirred at rt for 30 n-m and then neutralized with

K

2 CO3. The solution was extracted with Tiff/ethyl acetate. The organic layers were combined and washed with brine. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure. Purification by flash chrxomatography (15:1 CTLCl/ MeOH) afforded N-3.

1H NMR: 7.54 6.74 11-1), 2.45-2.52 (in, 1.46-1.97 (in, 14H).

Example 0 Procedure for Preparation of 4(5)-octahydro pentalen-2-ylmethyl)-lHim-idazole, hydrochloride: 0 PCC, CH 2 C1 2 reflux

LDA

H

0 H2S0 4 90 0

C

N

H

1) hydrazine, diethylene glycol 2) KOH 3) HCl, ether

H

N

HO N

H

H

H

2 Pd/C

N

HO

N

14

H

N

H 1

HCI

N

H

WO 02/076950 PCT/US02/08222 58 Procedure- A. Following the synthesis of White and Whitesell, Synthesis pp. 602- 3 (1975), ether (10 mL) was added to a flame-dried flask cooled to 0 C and then kept under an argon atmosphere. Then n-butyl lithium (35 mL of 2.5 M solution in hexane, 2.2 equiv.) was added and subsequently diisopropyl amine (14 mL, 2.5 equiv.) was added slowly and the mixture was allowed to stir for 30 min. at 0°C. To this generated solution of lithium diisopropyl amide was added cyclooctene oxide (5.0 g, equiv.). The mixture was stirred at rt for one day and then heated to reflux under argon atmosphere for 2 days. The reaction was quenched by addition of N-H4CC. The solution was extracted with THF/EtOAc.

The. organic extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford a yellow brown oil which was the 1-hydroxy-octahydropentalene. The compound was used without further purification in the next step.

B. The alcohol thus obtained (5.0 g, 1 equiv.) was dissolved in dichloromethane (200 mL) and to this solution was added pyridinium chlorochromate (13 g, 1.5 equiv.) and the mixture was stirred at rt for one day. The solution was then filtered through a short column of SiO2 using diethyl ether as eluent. The obtained solution was concentrated in vacuo to afford a pale green-yellow oil which was used without further purification in the next step.

C. The octahydro-pentalen-l-one (5.0 g, 1.0 equiv.) of the above step was added to 4(5)-imidazolecarboxaldehyde (3.8 g, 1.0 equiv.) and

H

2 S04 (20 ml) and the mixture was maintained at 90*C for 3 days. The reaction was then quenched by addition of ammonium hydroxide and extracted with tetrahydrofuran/ethyl acetate. The organic extracts were WO 02/076950 PCT/US02/08222 59 combined, washed with brine, dried over magnesium sulfate. The resulting aqueous layer was neutralized with HC1/ NH4CI. The aqueous layer was re-extracted as above and the combined organic fractions were concentrated in vacuo to afford an orange solid.

D. This orange solid was dissolved in ethanol to which palladium on carbon (0.5 g) was added. The reaction flask was placed under 40 psi of hydrogen for one day. The reaction solution was filtered though celite with more ethanol used as eluent. The solution was concentrated in vacuo to afford a yellow brown oil. Purification by column chromatography using 17:1 chloroform/methanol afforded the ketone product in a somewhat impure state.

E. The ketone functionality was then removed by addition of the product of the step above (8.2 g, 1.0 equiv.) to diethylene glycol mL)and hydrazine hydrate (13.0 g, 1.0 equiv.). This mixture was stirred overnight and then potassium hydroxide (11.0 g, 5.0 equiv.) was added and the solution was heated under reflux for one day. The reaction solution was cooled to rt and washed with water. The solution was extracted with THF/EtOAc and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil. The monohydrochloride salt was made by dissolving this oil in anhydrous ethanol saturated with HC1 and heating.

WO 02/076950 WO 02/76950PCT/US02/08222 Example P Procedure for the preparation of 7-(3H-imiddazol-4(5)-ylmethyl)-6,7dihydro-5H-isoquinolin-8-one and 7-(3H-imnidazol-4(5)-ylmnethyl)- 5,6,7, 8-tetrahydroisoquinoline (P-2) KMn04 ~C0 2

,H

C0 2

H

N

(minor) HCI, EtOH -~Co 2 Et

(N

COAE

N

(minor) 0 1) LDA 2) methyl actylate 40% HS0 OHC N

N

H

0 N C- C0 2 Me 0

N

NI NH 1) H 2 Pd/C 2) fumnaric acid

N)

N NH H 0 2 C 0 2 1) hydrazine diethylene glycol 2) KOH 3) fumnaric acid

INH

NN

WO 02/076950 PCT/US02/08222 61 Procedure: A. 3,4-lutidine (21.4g, 1 equiv.) was dissolved in 200 mL of water at 20 0 C and potassium permanganate was added in 6.32g portions twice daily for 5 days (total 63.2g, 2 equiv.). After 5 days the solution was stored in the freezer, then thawed and filtered through celite. The resulting colorless solution was concentrated at 0 C on a rotary evaporator until a white solid was obtained. This solid was recrystallized from 5N HC1 to give 9.56g of white crystals. NMR indicated a mixture of two regioisomers with the desired isomer being the major product.

B. These crystals were heated in anhydrous ethanol saturated with HC1 gas under argon and at reflux for 6 h. Then ethanol was removed from the solution by rotary evaporation and the residue was taken up in 100 mL of water and the pH was adjusted to between 7 and 8 with solid sodium bicarbonate. The aqueous phase was extracted with diethyl ether (3X) and the combined organic fractions were washed with brine, dried over magnesium sulfate and then filtered and concentrated to give a colorless oil (3.56g, 10.8% yield).

C. Diisopropylamine 2.84g, 1.3 equiv.) was added to n-BuLi (11.21 mL, 1.3 equiv.) in 100 mL of anhydrous THF under argon at -78 0 C via syringe to produce lithium diisopropylamide in situ. To this solution was added the product of B above (3.56g, 1 equiv.) in 20 mL of tetrahydrofuran, via syringe and the mixture was stirred at -78 0 C for 20 min. At this point methyl acrylate (4.85 mL 2.5 equiv.) in 20 mL of tetrahydrofuran was added dropwise through a cannula. The solution was stirred another 2 h before quenching by addition of 40 mL of 10% potassium acetate. The solution was allowed to warm to 20 0

C

and then was concentrated on a rotary evaporator. The aqueous residue was extracted three times with chloroform. The combined fractions were washed with brine and dried over magnesium sulfate, filtered and concentrated to a black solid, which was stored under high vacuum. Chromatography on silica gel WO 02/076950 PCT/US02/08222 62 with hexanes ethyl acetate (7/3 6/4) afforded 2.41g of the desired product which was used without further purification in the next step.

D. The material from Step C (0.48g, 1 equiv.) was dissolved in 1 mL of 6M HC1 and heated at 105 0 C for 16 h after which time the solution was concentrated to a solid by rotary evaporation at 80 0 C. The residue was taken up in 2 mL of water and neutralized with solid sodium bicarbonate. The neutralized solution was extracted with chloroform (3X) and the combined fractions were washed with brine, dried over magnesium sulfate and concentrated to a colorless oil. (0.45 6 g 93.4%).

E. The isoquinolone (1.91 g, 1 equiv.) obtained in step D above was heated with 4(5)-imidazolecarboxaldehyde 1.25g, 1. equiv.) at 110 0 C in 15 mL of sulfuric acid for 30 h. The reaction mixture was stored for several days at 0° C under argon. The solution was then diluted with 20 mL of water and basified to pH 8.9 with NH 4 0H. Solids were collected by filtration and dried with high vacuum. The product was a yellow solid (2.81g, 96.1%) comprising a mixture of both positional isomers at the exo double bond.

F. The product of E, above, was dissolved in 150 mL of methanol and to this solution Pd/C (.412g, 0.15 wt. equiv.) was added. The methanolic solution was then saturated with H2 by repeated evacuations and H 2 back-fill iterations. The solution was stirred under 1 atm. pressure of H 2 for 20 h until TLC revealed that no unsaturated starting material remained. The solution was filtered through celite and concentrated to an oil. Chromatography on silica using dichloromethane and methanol recovered pure product (1.853g 6504 as a white foam. This was taken up in methanol to which fumaric acid (0.4817g, 1.5 equiv.) was added with warming to dissolve the solids. The solution was cooled slowly and off-white crystals (0.826g, 74%) were obtained, which are represented as the compound P-l. P-2 was obtained by hydrazine reduction in the same manner as described in Step E of Example 0 above.

WO 02/076950 PCT/US02/08222 63 Example Q Procedure for the preparation of (Z)-6-(3H-imidazol-4(5)-ylmethylene)-7,8- (E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8dihydro-611-quinolin-5-one 6-(3H-imidazol-4(5)-yhnethyl)-7,8-dihydro- 6H-quinolin-5-one 6-(3H-imidazol-4(5)-ymethyl)-5 ,6,7,8tetrahydroquinoline, dihydrochioride and 6-(3H-imidazol-4(5)-ylmethyl)- WO 02/076950 WO 02/76950PCT/US02/08222 0 ON3 NaN 3

CH

3

CN,

C11

H

2 0, Na 2

S

2 0 3 DMF, NaN 3 CH7CI 2 Ph3fP, r chromatographic 0 0 purification to N3 6

N

3 desired isomer 0 acrolein 0 Pd/C (lN-M3I N

H

2 S0 4

OHCI

N

H

H

2 Pd/C MeOH Q-2 Q-1 0

N

HJ N Q-3 1) hydrazine diethylene glycol 2) KOH 3) HCI 2HC1

N-

Nf

HN

0

N

N N H H

A

ILi/NH 3 0

N

N N H H WO 02/076950 PCT/US02/08222 Procedure: A. The reactive azido reagent of the first step was generated in situ by addition of iodine monochloride (67.6 g, 1.15 equiv.) in 50 mL of acetonitrile dropwise through a dropping funnel to a stirred slurry of sodium azide (58.84 g, 2.5 equiv.) in 350 mL of anhydrous acetonitrile at -10 0 C and under argon.

Addition was complete in 30 min, the mixture was stirred an additional 30 min and cyclohexenone (34.81 g, 1.0 equiv.) was added via a syringe and then stirred at 20°C for an additional 20 h. The mixture was then poured into a liter of water and extracted with three 200 mL portions of diethyl ether. The combined fractions were washed with 5% sodium thiosulfate solution and then brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo at 20°C. The residues were taken up in 1 L of DMSO at o0C and a second portion of NaN 3 was added and the mixture stirred while warming to ambient temperature. This mixture was then diluted with 2.5 L of ice water and extracted ten times with dichloro-methane (10 X 250 mL). The combined organic fractions were concentrated on a rotovap to a volume of-~ L and this concentrate was extracted three times with 250 mL of water, and then brine, and then dried over magnesium sulfate and concentrated to a dark oil (39.5 g) and stored at -40 0

C.

The oil was purified by chromatography on silica using 9/1 to 8/2 hexane:ethyl acetate. Two isomers were recovered, the first with the azido group ac to the ketone function was obtained in 13.22 g, 26.6%, yield. The p-isomer was obtained in 15.825 g, 32.0%, yield.

B. Triphenyl phosphine was dissolved in 20 mL of dichloromethane and placed under an argon atmosphere at 20 oC. The p-isomer obtained as described above was added via cannual to the stirred solution and maintained at 20 0 C for 2 h. As the reaction progressed nitrogen was liberated from the solution, and after 2 h TLC demonstrated there was no starting material remaining. The solution was concentrated and passed through a silica gel column with WO 02/076950 PCT/US02/08222 66 dichloromethane progressing to 95/5 dichloromethane:methanol as eluent. The amidophosphonate intermediate was obtained in 2.139 g, 65.1%, yield.

C. The amidophosphonate was dissolved in 100 mL of anhydrous o-xylene and then 10% Pd C was added with stirring. Freshly distilled acrolein was then added to the mixture via syringe and heated to reflux for 4 h, after which time the remaining acrolein was added and heating under reflux was continued for 44 h under a finger condenser and under argon. At that time TLC indicated some intermediate remained, so 0.5g addition Pd/ C was added and the mixture again was heated to reflux for another 8 h. The mixture was cooled to rt, filtered and concentrated on a rotovap to eliminate excess acrolein, until about 100 mL of oxylene solution remained. This solution was cooled by addition of ice, and was extracted three times with IN HCI. The combined aqueous fractions were extracted 3X with Et 2 0. The aqueous phase was then cooled to 0°C and the pH was adjusted to -10 using concentrated NaOH. The aqueous was then extracted 5X with 100 mL portions of chloroform. The combined chloroform fractions were washed with water and then brined and dried over magnesium sulfate, filtered, and finally concentrated to give 3.51 g of an oil in 84.4% yield of 7,8- D. The 4(5)-imidazole carboxaldehyde was condensed with the quinolinone as described in Step E of Example P and was obtained both Q-1 and Q-2.

E. The exo double bond was then reduced with palladium on carbon as described in Step F of Example P above to yield two products which were separated by chromatography to give Q-3 and A.

F. The keto group was removed by the same hydrazine reduction procedure as that described in Step E of Example O above to give Q4.

G. The fully-reduced quinoline ring product Q-5 was obtained by a standard reduction of A with lithium/ammonia. (Li, 10 equiv., in NH 3 at -78 0 C for min, quenched with NH 4 0H, gradual warming with NH 3 evaporation).

WO 02/076950 PCT/US02/08222 67 Example R-1 Procedure for the preparation of (E)-6-(3H-imidazol-4(5)-ylmethylene)-7, 8- N Ac20, 170C S1- 2) 03, MeOH N OHC N 2) Me 2

S

N

0 0 N piperidine, AcOH N 1 OHC, CN

N

H R-l Procedure: A. A mixture of 5,6,7,8-tetrahydroquinoxaline (23.75g, 1 equiv.), benzaldehyde (19.81 mL, 1.1 equiv.) and acetic anhydride (33.4 mL, 2.0 equiv.) was stirred at 150 0 C under argon for 15 hr, after which time TLC indicated mostly desired product with some starting materials remaining. Starting materials were removed by vacuum distillation using a Vigreux column at 170 0 C. The pot residue was then subjected to Kugelrohr distillation from 170 220 0 C. The first fraction was slightly contaminated with starting materials (4.71g). A second fraction was pure (18.93g). After applying high vacuum to the first fraction it crystallized. Combined fractions yielded 20.11g, 51%.

B. The product from A, above, was dissolved in 100 mL of methanol and warmed slightly, then cooled to -35 to -40 0 C and ozone was bubbled through the solution. After a few minutes the starting material began to crystallize out of solution and the solution was warmed and another 200 mL of methanol was added and then the reaction was resumed. After about 30 minutes the solution turned pale blue. Nitrogen was then introduced by bubbling through the solution WO 02/076950 PCT/US02/08222 68 for 30 minutes, then methyl sulfide (3.5 mL) was injected into the solution, whereafter the solution was stirred for another 30 min. at -35 0 C, then allowed to warm to ambient temperature with stirring. After about 48 hr. at 20 0 C the mixture was steam distilled to remove solvents to provide a residue of 8.4g of a yellow-brown oil. This residue was taken up in diethyl ether and extracted 3x with 25 mL portions of 1N HC1. The combined aqueous fractions were washed with diethyl ether 3x. The aqueous solution was gradually basified to a pH of 8 with concentrated NaOH. The free amine was then extracted from the aqueous phase with chloroform The combined chloroform extracts were washed twice with brine, dried ofMgSO4 and concentrated to a yellow oil (3.01g) After keeping under high vacuum for 1 hr., 2.97g remained. This was recrystallized from diethyl ether to give 2.35g of a bright yellow solid. Yield 67.5%.

c. The 7,8-dihydroquinoxalin-5-one and (Aldrich Chemicals) were suspended in 75 mL of anhydrous tetrahydrofuran at 20 0 C under argon followed by addition of piperidine followed by acetic acid.

The mixture was stirred 16 h at 20 0 C. After 20 h, no traces of the quinoxalone remained as indicated by TLC. The solids were collected by filtration and washed with a small amount of tetrahydrofuran, followed by chloroform. The solid was dried under high vacuum to give 6.85g of R-1. Yield 90.3%.

Example R-2 and R-3 In a similar manner as R-l, 5,6,7,8-tetrahydroisoquinoline (5.42g, 1 equiv., Aldrich) was stirred with benzaldehyde (5.182 g, 1.2 equiv.) and acetic anhydride (6.309 g, 2.0 g) which was vacuum distilled and used without further purification in the next step. Yield (impure): 8.28 g.

The crude product (7.96 g) from the step above was subjected to ozonolysis as described in Step B above. After work-up and chromatography there was obtained 5.18 g of a pale oil. Yield: 97.8% assuming pure starting material.

WO 02/076950 WO 02/76950PCT/US02/08222 69 The resulting 7,8-dihydro-6H-isoquinolin-5-one (1.692 g, 1 equiv.) was condensed with 4(5)-imidazolecarboxaldehyde as described in Step C above to yield 2.23 g of the unsaturated compound analogous to R-1 in the scheme above in 92.8% yield. This product was treated with palladium on carbon as described in Step F of Example P to reduce the exo double bond to produce 6-(3Himidazol-4(5)-ylmethyl)-7,8-dihyclro-6H-isoquinolin-5-one in 52%.

The ketone above was reduced using hydrazine and converted to the famarate salt as detailed in Example P, Step F. Yield for the reduction: 62%. Yield of fumnarate salt after recrystallization: 30.4% of 6-(3H-ixnidazol-4(5)-yhnethyl)- 5,6,7,8-tetrahydroisoquinoline Example S Procedure for the preparation 4(5)-(4a-methyl-2,3,4,4a,5,6,7,8-octahydronaphthalen-2-yhnethyl)-1H-imidazole, but-2-enedioic acid salt: 0 I Witg -BN' 1 OSI K{2HC 2) NH 3 MeOH 1 2 3) Fumaric acid N fUMarate H0 2

CZ

HNZ

C,

4 Procedure Methyl triphenylphosphoniuin bromide (2.75 g, 7.70 mmol) was suspended in 50 niL of diethyl. ether. At -10, nBuLi (3.08 rnL, 7.70 mmol, soin in hexanes) was added. This mixture was stirred for 35 m before cooling to -70 A solution of (R)-(+)-4,4a,5,6,7,8-hexahydro-4a-methyl- 2(3H)-naphthalenone (1.0 g, 6.09 nunol) in 15 niL of ether was added via syringe. This mixture was warmed to 0 0 C over 30 m and the stirred at rt for WO 02/076950 PCT/US02/08222 another 30 m. The solution was washed with brine (2 x 20 mL) dried over MgSO 4 filtered and the solvent was removed. Chromatography on SiO 2 with hexanes gave 0.82 g of the diene 2 as a clear colorless oil.

This hydroboration procedure follows that by Brown, H. C. et. al. J. Am.

Chem. Soc. 1969, 91, 2144. To a solution of the diene 2 (750 mg, 4.63 mmol) in 20 mL of THF was added 9-BBN (11.8 mL, 5.9 mmol, of a 0.5 M soln. in THF) at 0 oC. This was warmed to rt after 30 m and allowed to react at rt for 1 h. Dry MeOH (3.75 mL, 15.0 mmol as a 4.0 M soln in THF) was added to a stirred solution of LiAlH4 (5.04 mL, 5.04 mmol, 1.0 M in ether) to form LiAIH(OMe)3. The borane was added to this alkoxy aluminum hydride via syringe. After 10 m at rt, carbon monoxide was bubbled through the solution for 20 m. Phosphate buffer (25 mL, pH 7.0 was added followed byH 2 0 2 mL, 30% soln) and this was stirred for 30 m. After a typical extraction process the oil was purified by chromatography on SiOz with 5 to 10% EtOAc:Hx to yield the colorless aldehyde 3 as the major product 455 mg, This preparation followed the protocol by Home, D. Yakushijin, K.; Biichi, G. Heterocycles, 1994, 39, 139. A solution of the above aldehyde 3 (450 mg, 2.34 mmol) in EtOH (8 mL) was treated with tosylmethyl isocyanide (TosMIC) (430 mg, 220 mmol) and NaCN (~15 mg, cat) at rt for 20 m. The solvent was removed in vacuo and the residue dissolved in MeOH saturated with NH 3 (10 mL). The solution was heated in a resealable tube at 110 OC for 6- 12 h. The material was concentrated and purified by chromatography on SiO 2 with 5% MeOH (sat. w/ NH 3

:CH

2 C1 2 to give the imidazole as a thick glass 193 mg The imidazole was purified further by stirring in THF or MeOH with an equimolar amount of fumaric acid at rt for 10 m. The solvent was removed and the salt recrystallized by dilution in THF and tituration with ether:hexanes for a 70-80% recovery of pure fumarate 4 WO 02/076950 WO 02/76950PCT/US02/08222 71 '11 NMR (500 MHz, DMSO-d 6 w/ TMS): 8 7.73 1 6.83 I 6.60 (s, 21-1), 5.12 1 2.45-2.44 (in, 2 2.30 (brs, 1 2.12 (brs, 1 1.91- 1.88 (mn, 1 1.73-1.71 (in, 1 1.56-1.46 (in, 5 1.30-1.09 (series of m, 4 1.01 3H) 1 3 C (125 DMSO-d 6 w/ TMS) 167.0, 143.5, 134.8, 134.5, 128.7, 123.7, 118.2, 42.3, 36.7, 35.0, 32.8, 32.5 28.4, 25.9, 24.4, 22.3.

Example T-1 Procedure for the preparation 4(5)-(3-methyl-cyclohex-2-enyhnethyl)-1Hiniidazole, but-2-enedioic acid salt: 0 0 OH EVE LiAiH 4 Hg(OAC) 2 LiC1O 4

H

4NaOAc ether 12 3 4 1)TOSMIC fumarate 2) NH 3 MeOH HN 3) Fumaric acid Procedure A solution of 3-methyl-2-cyclohexen-1-one (5g, 45.4 ninol) in 25 niL of ether was added dropwise via an addition funnel to a solution of LiAIII 4 (45 niL, 1M in TL{F) in ether (100 niL) at -10 After 1 h the mixture was carefully quenched with NII 4 Cl (10 mL) and treated with 10% HCI1(7 niL).

The organic layer was extracted with ether (3 x 70 niL), dried over MgSO 4 filtered and concentrated. The residue was purified by chromatography by elution with 20% EtOAc:Hx to give 2, a clear colorless alcohol, 4.46 g WO 02/076950 PCT/US02/08222 72 A solution of alcohol 2 (1.68 g, 15 mmol) in ethyl vinyl ether (38 mL) was treated with Hg(OAc) 2 (3.2 g, 10 mmol) and NaOAc (410 mg, 5 mmol) at OC for 4 h. The mixture was poured onto 5% KOH solution (15 mL), diluted with ether and extracted with hexanes. The organic layer was dried over Na 2

SO

4 filtered and concentrated. The crude residue was used in the next step without further purification.

According to the procedure by Greico, P. et al, J. Am Chem. Soc. 1991, 113, 5488, a 3M solution of LiC10 4 (16 g, 150 mmol) in 50 mL of ether was treated with the crude vinyl ether 3 at rt for 30 m. The entire mixture was poured onto sodium bicarbonate solution (150 mL). After extraction of the aldehyde 4 with ether, the organic layer was dried over MgSO 4 filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography on SiO2 with EtOAc:Hx or submitted to the Biichi protocol as described above for the formation of the imidazole-fumarate 5 from 6 to free base of 'H NMR (500 MHz, d 6 -DMSO w/ TMS) 8 7.71 1 6.82 1 6.61 (s, 2 5.27 1 2.46-2.32 (series of m, 3 1.85 (brs, 2 1.60 3 H), 1.35-0.86 (series of m, 4 H) 1 3 C (125 MHz, DMSO-d 6 w/ TMS) 8 167.3, 134.9,134.5, 125.5, 118.1, 35.5, 32.6, 30.1, 28.5,24.0,21.4.

Example T-2 4(5)-(3,5,5-trimethyl-cyclohex-2-enylmethyl)-1H-imidazole, but-2-enedioic acid salt is prepared by substituting isophorone in the method of T-1 Example T-3 4(5)-(3-methyl cyclopent-2-enylmethyl)-IH-imidazole, but-2-enedioic acid salt is prepared by substituting 3-methyl-2-cylopenten-l-one in the method of T-1 WO 02/076950 PCT/US02/08222 73 Example U-1 Procedure for the preparation 4(5)-cyclohex-2-enylmethyl-lH-imidazole, but-2enedioic acid salt: 0

OH

LiAIH 4 MeC(OEt) 3 OY f0 DIBAL 0 140

*C

1 2 3 4 1) TOSMIC N fumarate 2) NH 3 MeOH HN 3) Fumaric acid Procedure A solution of cyclohexenone (2.88 g, 30 mmol) in hexanes at -78 °C was treated with DIBAL (30 mL, 1.0 M in cyclohexane). After 25 m, MeOH (7 mL) was added and the mixture was warmed to rt. A saturated solution of Rochelle's salt was added followed by dilution with ether (100 mL). The organic layer was separated, dried over MgSO 4 filtered and concentrated under vacuum. The product was purified by chromatography on SiO 2 with EtOAc:Hx to give a clear colorless alcohol 2, 2.0 g A solution of the above alcohol 23 (2.0 g, 20.4 mmol) in triethyl orthoacetate (30 mL) and propionic acid (~0.025 mL, cat) was heated to remove ethanol. After the ethanol was removed heating was continued at 145 OC for 1 h. The triethyl orthoacetate was removed by simple distillation. After the residue cooled to rt the product was purified by chromatography on SiO2 with ether:Hx to give ester 3 as a clear colorless oil 1.08g A solution of the above ethyl ester 3 (1.0 g, 5.9 mmol) was dissolved in hexanes (50 mL) and cooled to -78 A solution of DIBAL (5.8 mL 1.0 M in cyclohexane) was added dropwise. After 15 m, diethyl ether (50 mL) was added WO 02/076950 WO 02/76950PCT/US02/08222 74 and the mixture was stirred with Rochelle's salt solution (25 mL) for 10 mn. The organic layer was separated, dried and filtered. Chromatography on SiO 2 with 7% Et 2 O:Hx delivered the aldehyde as a clear colorless oil, 0.52g The aldehyde 4 was subjected to the Bu~chi protocol as described above. The fumarate salt of the imidazole 5 was obtained in three steps (25% overall).

'H NMR (500 MiHz, DMSO-d.

6 w/ TMS) 7.67 1 6.80 1 HI), 6.60 (s, 2 5.66-5.54 (in, 2 2.52-2.42 2 2.34 (brs, 1 1.93 2 1.66 (brs, 2 1.46-1.43 (mn, 1 1.22-1.16 1 H) 13 C (125 NMz, DMSO-d 6 w/ TMS) 166.3, 134.3, 134.2, 131.2, 126.9, 118.1, 96.5, 35.0, 32.5, 28.4, 24.8, 20.7.

Example U-2 4(5)-(4-methyl-cyclohex-2-enyhnethyl)-H-ilidazole, but-2-enedioic acid salt is prepared by substituting 6-methyl-2-cyclohexen-1-one in the method of U-1 Example V Procedure for the preparation of 2-(lH-lnaidazole-4(5)-ylinethyl)cyclohexanone, but-2-enedioic acid salt: 04% OHC.. piperadine NHN1) Pd-C/HB 2 K) HNt;.N AcH/TF2) fumaric acid N 2.

Procedure To the 4(5)-inidazolecarboxaldehyde (2.52 g, 26.23 rmol) suspended in cyclohexanone (25.74 g, 262..25 inmol) under argon added the piperadine (0.56 g, 6.56 minol) and acetic acid (0.52 g, 8.65 inmol). After heating at reflux for 16 h. the cyclohexanone was removed by kugelrobr. Chromatography on WO 02/076950 PCT/US02/08222 SiO 2 with 5-10% MeOH (saturated with NH3): CH 2 C12 gave 4.07 g of unsaturated imidazole 1 as an oil.

The unsaturated imidazole 1 (1.02 g, 5.81 mmol) in MeOH (40 ml) containing palladium (10 wt. on activated carbon) (0.15 g) was hydrogenated at 1 atmosphere pressure of H 2 After 16 h the palladium was filtered off and the filtrate was concentrated at reduced pressure. The imidazole was recrystallized by stirring in MeOH with an equimolar amount of fumaric acid until all solids had disappeared followed by the addition of a small amount of diethyl ether and cold storage. The title compound 2 0.80 g was recovered as white crystals.

1 H NMR (300 MHz, CDC1 3 w/ TMS) 6 9.5-6.5 (vbs, 3H), 7.71(s, 1H), 6.80 (s, 1H), 6.60 2H), 2.91(dd, J 14.8 Hz, J 5.4 Hz, 1H), 2.75-2.60 1H), 2.42-2.28 2H), 2.27-2.17 1H), 2.02-1.89 2H), 1.78-1.68 1H), 1.68-1.45 2H), 1.32-1.17 1H) 13C NMR (75MHz, DMSO-d 6 w/ TMS) 6 211.6, 166.6, 134.4, 134.2, 133.8, 117.4, 49.7, 41.4, 33.1, 27.5, 25.8, 24.3.

WO 02/076950 PCT/US02/08222 76 Example W-1 Procedure for the preparation of 4(5)-(3,4-Dimethyl-cyclohex-3-enyhnlmethyl)- IH-imidazole, but-2-enedioic acid salt X CO2Et sealed tube 175 0 C/ 18h

CO

2 Et 1

LAH

THF

2 Ph) 3 P? imid.

12 benzene Me) 2 N802-N tBDMSi 4 1) 5M KOH reflux 2) fumnaric acid 3

TBAF

TBF

f=\ Me) 2 NS0 2

-NIN

tBDMSi nBuLi Me) 2 NS0 2

N

HN

<Y(

fumarate 6 Procedure 2,3-Dimethyl- ,3-butadiene (10.16 g, 123.72 mmol), ethyl acrylate (11.06 g, 110.47 mmol) and hydroquinone (0.12 g, 1.11 mmol) were heated with stirring at 1650C in a sealed tube for 16 h and then at 2050C for an additional 4 h. Kugelrohr distillation of the resulting residue at 1500C and torr gave 14.11 g of cyclohexene ester 1 as an oil in the 20 0 C bulb. To a solution of the ester 1 (13.62 g, 72.32 mmol) in anhydrous THF (200 ml) at 780C under argon added the LiAIH 4 (54.30 ml, 1 M in diethyl ether). This WO 02/076950 PCT/US02/08222 77 mixture was stirred for 1 h at 20 0 C and then quenched at 0 C by the careful, consecutive addition of H20 (2.06 ml), NaOH (2.06 ml of a 15% aqueous solution), and an additional portion of H 2 0 (6.18 ml). The solids were filtered off and the filtrate was concentrated under reduced pressure. Kugelrohr distillation of the resulting residue at 150-180 0 C and 0.5 torr gave 9.98 g (98%) of the alcohol 2 as a colorless volatile oil in the 0°C bulb. To a solution of triphenyl phosphine (27.13 g, 103.45 mmol), and imidazole (7.04g, 103.45 mmol) in anhydrous benzene (450 ml) under argon was added the 12 (22.75 g, 89.61 mmol) in benzene (170 ml) over a period of 10 minutes with rapid mechanical stirring. After an additional 10 minutes the alcohol 2 (9.23 g, 65.89 mmol) in benzene (100 ml) was added to this rapidly stirring mixture over a period of 5 minutes. After 2 h the reaction was diluted with hexanes (800 ml) and the solids were filtered off. The organics were washed with 3 portions of (800 ml), dried (MgSO 4 filtered and concentrated under reduced pressure.

The residual solids were filtered off and the resulting oil was purified by kugelrohr distillation at 200 0 C and 0.5 torr to give 11.99 g of the iodide 3 as a pale oil in the 0 C bulb. To a solution of the previously described 1- N- (dimethylsulfamoyl)-2-tert-butyldimethylsilyl imidazole (4.34 g, 15.00 mmol) in anhydrous THF (50 ml) at -78 0 C under argon was added n-butyllithium (5.76 ml, 2.5 M in hexanes). This mixture was stirred for 10 minutes at -10 0 C and then cooled to -20 0 C before adding the iodide 3 (3.00 g, 12.00 mmol) in THF ml) dropwise via cannula. The resulting solution was stirred for 16 h at 0 C, then quenched with saturated aqueous NaHCO 3 and concentrated under reduced pressure. The residues were taken up in diethyl ether and washed consecutively with HzO and brine, dried (MgSO4) and concentrated.

Subsequent purification by chromatography on SiO 2 with 5-10% EtOAc:hexanes gave 0.89 g of the imidazole 4 as a pale oil. To a solution of imidazole 4 (0.89 g, 2.17 mmol) in anhydrous THF (25 ml) under argon was added tetrabutylammonium fluoride (2.38 ml, 1 M in THF) and the resultant WO 02/076950 PCT/US02/08222 78 solution was stirred for 1 h at 20 0 C. The mixture was concentrated under reduced pressure and the residues were taken up in diethyl ether and washed consecutively with saturated aqueous NaHCO 3 and brine, dried (MgSO4) and concentrated. The residues were purified by chromatography on Si02 with EtOAc:hexanes to give 0.56 g of the imidazole 5 as a pale oil. To a solution of 5 (0.53 g, 1.77 mmol) in MeOH (5 ml) was added aqueous KOH ml of a 5M solution) and the mixture was heated at reflux for 32 h. The mixture was concentrated under reduced pressure, diluted with H20 (5 ml) and extracted exhaustively with CHC1 3 The combined organic fractions were washed consecutively with H20 and brine, dried (MgSO4) and concentrated under reduced pressure. The imidazole was recrystallized by stirring in MeOH with an equimolar amount of fumaric acid until all solids had disappeared followed by the addition of a small amount of diethyl ether. The title compound 6 (W-1) 0.27 g was recovered as pale crystals.

1 H NMR (300 MHz, DMSO-d6 w/TMS) :5 10.3-8.8 (vbs, 3 7.88 1H), 6.89 1H), 6.59 2H), 2.48 J 6.7 Hz, 2 2.00-1.70 4 1.70- 1.57 2 1.56 3 1.54 3 1.21-1.04 1 H) 3 C NMR (75MHz, DMSO-d 6 w/ TMS) 5 166.7, 134.4,134.1,133.4, 124.8, 124.3, 117.9, 37.6, 34.1, 32.2, 31.1, 28.7, 19.0, 18.7.

Example W-2 4(5)-Cyclohex-3-enylmethyl-lH-imidazole, but-2-enedioic acid salt is prepared by substituting 3-cyclohexene-l-methanol in the method of W-1 WO 02/076950 PCT/US02/08222 Example X-1 Procedure for the preparation of 4(5)-(4-Methyl-cyclohex-3-enylmethyl)-lHimidazole, but-2-enedioic acid salt: WO 02/076950 WO 02/76950PCT/US02/08222 0 0 MeO0POM, NaH THF 0 0 0 PdICI/H2 MeOl 0 Ome 0 0 2 'Ali

['HF

O0H 3 oxalyl chloride DMSO Et 3

N

CH(

4

%_I

0 1) TosMIC NaCN 2) NI- 3 McOH Me 2

NSO

2

CI

E

3 N DMF Me,

HN

INHC 1101- 6 Ni, a N02S/ 'ZNf 7 0 THF Me 2

NO

2 S Burgess Rgt.

KOH 1120 'MeOH reflux 1) 1,2-dichloroethane TosH 2) Fumaric Acid recryst.

13 fumarate WO 02/076950 PCT/US02/08222 81 Procedure To a slurry of NaH (60% in oil) (6.92 g, 288.28 mmol) in anhydrous THF (1500 ml) at 0 C under argon with vigorous mechanical stirring added the trimethyl phosphonoacetate (52.50 g, 288.28 mmol) dropwise. Stirred this mixture an additional 30 minutes before adding the 1,4-cyclohexanedione mono-ethylene ketal (40.93 g, 262.07 mmol) in THF (170 ml) dropwise. The mixture was stirred an additional 18 h at 20 0 C and then concentrated under reduced pressure. This residue was taken up in diethyl ether (1000 ml) and washed consecutively with H 2 0 and brine, dried (MgSO 4 filtered and concentrated to give 60.08 g of the unsaturated ester 1 which was carried on without further purification. To a solution of unsaturated ester 1 in EtOAc (500 ml) added the palladium (10 wt. on activated carbon) (2.13g). This slurry was saturated with H2 by repeated evacuations and H2 backfills and then stirred for 16 h under one atmosphere pressure of H 2 Celite (5 g) was added to the reaction, the palladium was filtered off and the filtrate was concentrated under reduced pressure to give 59.45 g of the saturated ester 2 which was carried on without further purification. To a solution of LiAIH 4 (200.00 ml, 1 M in diethyl ether) at -78 0 C under argon was added the unsaturated ester 2 in anhydrous THF (400 ml) in a slow stream with vigorous mechanical stirring.

Upon warming to 20 0 C additional THF (600 ml) was added and the reaction was stirred 1 h. The mixture was cooled to 0 C and quenched by the careful, consecutive addition of H 2 0 (7.60 ml), NaOH (7.60 ml of a 15% aqueous solution), and an additional portion ofHzO (22.80 ml). The solids were filtered off and the filtrate was concentrated under reduced pressure. Subsequent purification by chromatography on SiO 2 with 20-50% EtOAc:hexanes gave 50.93 g of the alcohol 3 as a pale oil. To a solution of oxalyl chloride (20.65 ml, 41.29 mmol) in anhydrous CH 2 C2 (100 ml) at -78 0 C under argon was added dropwise a solution of DMSO (6.72 g, 86.02 mmol) in CH 2 C2 ml). After mechanical stirring for 15 minutes a solution of the alcohol 3 (6.40 g, WO 02/076950 PCT/US02/08222 82 34.41 mmol) in CH 2 C1 2 (80 ml) was added dropwise and the mixture was stirred an additional 15 min at -78 0 C before adding triethylamine (27.85 g, 275.30 mmol). The reaction was stirred 2 h at 20 0 C and then quenched with saturated aqueous NaHCO 3 This mixture was extracted CH 2 C12 and the combined organic fractions were washed consecutively with H 2 0 and brine, dried (MgS04) and concentrated under reduced pressure. The resulting solids were purified by chromatography on SiO 2 with 20-30% EtOAc:hexanes to give 5.08 g, of the aldehyde 4 as a white solid. A solution of aldehyde 4 (5.08 g, 27.59 mmol) in EtOH (40 ml) was treated with tosylmethyl isocyanide (TosMIC) (5.15 g, 26.27 mmol) and NaCN (0.13 g, 2.68 mmol)'at 20 0 C for 3 h and then refrigerated. After 2 h refrigeration the solids were filtered off, dissolved in anhydrous MeOH saturated with NH3 (30 ml) and heated in a sealed tube at 100 0 C for 3.5 h. The reaction was then concentrated under reduced pressure and the residues were taken up in CHCbI, washed consecutively with saturated aqueous NaHCO 3 and brine, dried (MgSO4) and concentrated to a red oil. This residue was further purified by chromatography on SiO 2 with 5-10% MeOH (saturated with NH 3 CHzC1 2 to give 1.87 g (31%) of the imidazole 5 as a pink oil. A solution of 5 (0.55 g, 2.48 mmol) in acetone ml) containing HCI (5 N, 0.5 ml) was stirred for 5 h. The reaction was concentrated under reduced pressure, the residues were taken up in H 2 0, neutralized to pH 7 with saturated aqueous NaHCO 3 and extracted exhaustively with CHCl 3 /isopropyl alcohol The combined organic portions were washed consecutively with H20 and brine, dried (MgSO 4 and concentrated.

Chromatography on SiOz with 5-10% MeOH (saturated with NH 3 CH2Clz gave 0.43 g of the desired ketone 6. A solution of 6 (0.20 g, 1.11 mmol).

in anhydrous DMF (4 ml) under argon was treated with triethylamine (0.14 g, 1.33 mmol) and dimethylsulfamoyl chloride (0.19 g, 1.33 mmol) under argon and stirred 16 h. The solids were filtered off and the filtrate was concentrated at via kugelrohr at 100 0 C and 0.5 torr. The residues were taken up in CHC13 and WO 02/076950 PCT/US02/08222 83 washed consecutively with H 2 0 and brine, dried (MgSO 4 and concentrated.

Chromatography on SiO 2 with 1-5% MeOH:CH2C12 gave 0.22 g of the desired protected imidazole 7 as a mixture of regioisomers which were carried on without separation. A solution of 7 (0.18 g, 0.62 mmol) in anhydrous THF (10 ml) under argon was treated with methylmagnesium chloride (0.32 ml, M in THF) and the resulting mixture was stirred 16 h. The reaction was quenched with a small amount of MeOH, concentrated under reduced pressure and the residues were taken up in H20. The mixture was acidified by the dropwise addition of 1 N HC1 until the solution was homogenious and then the pH was adjusted to 7 with saturated aqueous NaHCO3. The organic materials were extracted into CHC13 and the combined organic portions were washed consecutively with H20 and brine, dried (MgSO 4 and concentrated.

Chromatography on SiO 2 with 5% MeOH:CH 2 Cl 2 gave 0.18 g of the alcohol 8 as a mixture of regioisomers which were carried on without separation. A solution of 8 (0.14 g, 0.46 mmol) in anhydrous benzene (3 ml) at 0°C under argon was treated with (methoxycarbonylsulfamoyl) triethylammonium hydroxide, inner salt (Burgess reagent) (0.12 g, 0.51 mmol) and stirred 1 h at 200C. The reaction was concentrated under reduced pressure and subsequent purification by chromatography on SiO 2 with MeOH:CH 2 Cl2 gave 0.12 g of the alkenes 9 and 10 as a mixture of isomers which were carried on without separation. The mixture of isomers 9 and 10 (0.12 g, 0.42 mmol) were refluxed in a solution composed ofMeOH (2 ml) and KOH (2 ml of a 5 N solution) for 30 h. The reaction was concentrated under reduced pressure and the residues were taken up in H20 and extracted exhaustively with CHC1 3 The combined organic portions were washed consecutively with H20 and brine, dried (MgS04) and concentrated.

Chromatography on SiO2 with 5-10% MeOH (saturated with NH 3

CH

2 C2 gave 0.05 g of alkenes 11 and 12 as a mixture of isomers which were carried on without separation.

WO 02/076950 PCT/US02/08222 84 The mixture ofalkenes 11 and 12 (0.045 g, 0.26 mmol) and p-toluenesulfonic acid hydrate (0.063 g, 0.32 mmol) were heated at reflux in 1,2-dichloroethane (2 ml) under argon for 20 h. The reaction was concentrated under reduced pressure and the residues were purified by chromatography on SiO 2 with 10% MeOH (saturated with NH3): CH 2 C1 2 to give the free base of imidazole 13 as one isomer. The imidazole was recrystallized by stirring in MeOH or THF with an equimolar amount of fumaric acid until all solids had disappeared followed by the addition of a small amount of diethyl ether and cold storage. The title compound 13 0.040 g was recovered as white crystals.

1 H NMR (300 MHz, DMSO w/ TMS) 8 7.65 1 6.78 1 6.60 2 5.31 1 2.44 J 6.7 Hz, 2 2.02-1.82 3 1.82-1.60 3 1.59 3 1.26-1.11 1 H) 3 C NMR (75MHz, DMSO-d 6 w/ TMS) 6 175.0, 165.2, 134.3, 134.1, 133.2, 120.3, 118.3, 33.2, 32.4, 31.2,29.3, 28.3, 23.4.

Example X-2 4(5)-(4-Ethyl-cyclohex-3-enylmethyl)-lH-imidazole, but-2-enedioic acid salt is prepared by substituting ethyl magnesium chloride in the method of X-l Example X-3 4(5)-(4-Pentyl-cyclohex-3-enylmethyl)-lH-imidazole, but-2-enedioic acid salt is prepared by substituting pentyl magnesium chloride in the method of X-l Of course, in light of the detailed synthetic schemes disclosed within the present specification methods of making other compounds falling within the claims of the present specification will be clear to the skilled chemist.

WO 02/076950 PCT/US02/08222 Example Y A method for measuring a-agonist selectivity comprises the RSAT (Receptor Selection and Amplification Technology) assay as reported in Messier et al. (1995) "High throughput assays of cloned adrenergic, muscarinic, neurokinin and neurotrophin receptors in living mammalian cells", Pharmacol. Toxicol. 76:308-11 and adapted for use with alpha2 receptors. The assay measures a receptor-mediated loss of contact inhibition that results in selective proliferation of receptorcontaining cells in a mixed population of confluent cells. The increase in cell number is assessed with an appropriate transfected marker gene such as b-galactosidase, the activity of which can be easily measured in a 96-well format. Receptors that activate the G protein, Gq, elicit this response. Alpha2 receptors, which normally couple to Gi, activate the RSAT response when coexpressed with a hybrid Gq protein that has a Gi receptor recognition domain, called Gq/i5 2 See Conklin et al. (1993) "Substitution of three amino acids switches receptor specificity of Gqa to that of Gia." Nature 363:274-6.

NIH-3T3 cells are plated at a density of 2x10 6 cells in 15 cm dishes and maintained in Dulbecco's modified Eagle's medium supplemented with 10% calf serum. One day later, cells are cotransfected by calcium phosphate precipitation with mammalian expression plasmids encoding p-SV-b-galactosidase (5-10 mg), receptor (1-2 mg) and G protein (1-2 mg).

mg salmon sperm DNA may also be included in the transfection mixture. Fresh media is added on the following day and 1-2 days later, cells are harvested and frozen in 50 assay aliquots. Cells are thawed and 100 ml added to 100 ml aliquots of various concentrations of drugs in triplicate in 96-well dishes. Incubations continue 72-96 hr at 37. After WO 02/076950 PCT/US02/08222 86 washing with phosphate-buffered saline, b-galactosidase enzyme activity is determined by adding 200 ml of the chromogenic substrate (consisting of 3.5 mM o-nitrophenyl-b-D-galactopyranoside and nonidet P-40 in phosphate buffered saline), incubating overnight at and measuring optical density at 420 nm. The absorbence is a measure of enzyme activity, which depends on cell number and reflects a receptor-mediated cell proliferation. The ECso and maximal effect of each drug at each alpha2 receptor is determined. The efficacy or intrinsic activity is calculated as a ratio of the maximal effect of the drug to the maximal effect of a standard full agonist for each receptor subtype.

Brimonidine, also called UK14,304-18, is used as the standard agonist for the alpha2A and alpha 2 c receptors. Oxymetazoline is the standard agonist used for the alpha2B receptor.

Table 1, below, provides the intrinsic activity values at subtypes of the a2-adrenoreceptor as determined in the RSAT assay for the compounds of above Examples B through X and certain adrenergic compounds not having selective agonist activity at the a2B or a2B /a2C subtype(s). At the a2A subtype, the compounds of the Examples are inactive or exhibit low efficacy They have greater efficacy at the a2B and the c2C- subtypes than the a2A-subtype. Therefore, unlike ophthalmic a2-adrenoreceptor compounds such as clonidine and brimonidine, the compounds of Examples B through X can selectively activate a2-adrenoreceptor subtypes other than the a2A-subtype.

WO 02/076950 WO 02/76950PCT/US02/08222 87 Table 1: Intrinsic Activity Relative to Brimonidine/Oxymletazolifle Exaniple structurefComnpountl TBrimonidine Oxymetazoline B9rinionidine Alpha 2A Alpha 2B I Alpha 2C

I

__I

0.63 oxymetazoline 1.0 0.58 I t I n~,r u. ie 'J.IJ

'J..J.J

-lonidmne U.10 V.Ij

.I

0.93 brinionidmne I I 0.43 4(5)-(3-methyl-thiophefl-2ylmethyl)-IHiniidazole 4 D-3 N- 0 bicyclo[2.2. 1]hept-2-yl oxazolidin-2-ylidene amine I WO 02/076950 WO 0/07950PCT/UJS02/08222 [Example: Structure/Compound Brimonidine Oxymetazolint Brimolnidint Alpbfa 2A Alpha 2B A ia 2C D-l' 0 0.47 0 oxazolidin-2-ylidene-(3-phenyl bicyclo [2 1]hept-2-yl) amine F NH 0O 0.3 0.9 0.2 N N NLO H

H

6-(imnidazolidin-2-ylidene aniino)-5-niethyl-4H1benzo[1 ,4]oxazin-3-one G HCI 0.1 0.87 0.33 N N NH H methyl-3,4-dihydro-2Hbenzo[1 ,4]oxazin-8-yl) amnine, hydrogen chloride salt J1 1 N0.1 0.83 0 H N,' lHimidazole WO 02/076950 WO 0/07950PCT/UJS02/08222 Example Structure/Compound Brirnonidine Oxyitazoline 'Brimonidine IAlpha 2A Alpha 2B Alpha 2C E-1 NH 0.33 0.83 0.35 N N N H I imiaazolidin-2-ylidene-(4methyl-3,4-dihydro-2Hbenzo[ 1,4)oxazin-6-yl) amine M N 0 0.2 0.97 0.27

NDKK

H

4-(2,3-diliydro benzo[1 ,4]dioxin-6-ylmnethYl)- 5-mcthyl-1H-imidazole C-2 frN 0.23 1.3 s 4(5)-fbiophen-2-ylmethyl-1Himidazole C-1 pN 0 0.83 0 4(5)-tbiophen-3-ylmethyl-1Himidazole C-9 N 0.06 0.88 0.43 4(5)-benzo[b~thophen-2yhnethyl-1H-iniidazole WO 02/076950 WO 0/07950PCT/UJS02/08222 Example I Structure/Compound Brimnixidine Oxymnetazoline Brinionidine Alpha 2A Alpha 2B IAlipha 2C C-3 1N 0.1 0.88 0.43 HN7 4(5)-(5-niethylthiophen-2yhmethyl)-1H-im-idazole 0.3 0.9 0.4 tIN, 4(5)-benzyl-1H-imidazole H )111110.2 0.93 0.15 4(5)-phenylsulfany1-1Himidazole =N 0 1.1 0.4.

HI,- 0 4(5)-ftma-2-ylmethyl-lHim-idazole B-_b 0 0.7 0 ,2,3,4tet-ahydronaphthalen-2yhmethyl)-111-iinidazole J-2 ffN I 0 0.8 0 WO 02/076950 WO 02/76950PCT/US02/08222 Exapl Stucur/Copond Brimouidine Oxyrnetazoline Brimonidine Exaple Stuctre/omoinnd Alpha 2A Alpha 2B IAlpha 2C tetrahydronaphthalen-2yhnethyl)-1H-imidazole J-3 f--N K f 0.1 1 0.15 ,2,3,4tetrahydronaphthalen-2ylmethyl)-1H--imidazole L Hf, 0.23 0.9 0.57 4(5)-(1-fuan-2-ylethyl)-1Himidazole C-6 N 0.2 0.67 0.1 HNc z 4(5)-fmifan-3-y~methyI-1Hiniidazole C-4 k 0.05 0.82 HN4

C,

4(5)-(5-chlorotbiophen-2ylmethyl)-1H-iniidazole WO 02/076950 WO 0/07950PCT/UJS02/08222 Example f Structure/Compound Brimonidiine Oxymetazoline IBrimonidine Alpha 2A Alpha 2B Alpha 2C D-2 0.25 0.75 0

NO

oxazolidin-2-ylidene-(3-0-tolyl bicyclo [2.2.1 ]hept-2-yl) amnine 0-0-0.05 0.48 0.1 4(5)-benzofuiran-2-yhnethyl- 1H-imnidazole 07fN 0.08 0.73 0.2 4(5)-(5-methylfUran-2ylmethyl)- lH-imidazole B-3a Ht.. 0,1 0.8 0.07 0 2-(lH-irnidazol-4(5)ylmethyI)-3,4-dihydro-211naphthalen- I-one

CH

3

SO

3 H- 0 0.5 0.2

HN

WO 02/076950 WO 0/07950PCT/UJS02/08222 [Ex ample Structure/Compound BrImouidint Oxyietazoline Brhi in ,2,3,4tetrahydronaphthalen-2- Ilimidazole, methane sulfonic acid salt B-2a. N 0 0.63 0.15 HT, 0 3-(lH-inuidazol-4(5)yhnethylene)chroman-4-one B-2b 0 0 0.77 -0

HN/

0 3-(1ll-iniidazol-4(5)yhnethyl)chroman-4-one B-2d 0 0 0.6 0 H N- 4(5)-chroman-3-yhlmethyl-lHimidazole B-2 H_ 0 0 0.65 0

OH

3-(1H-imidazol-4(5)ylniethyl)chroman-4-ol WO 02/076950 WO 02/76950PCT/US02/08222 Example I Structure/Compouli irmonidine Oxymetazoline Brimonidine Alpha 2A Alpha 2B Alpha 2C ylmethyl)-1H-imnidazole 4(5)-(4-methyl-1 ,2,3,4tetrahydronaphthalen-2yhmethyl)-lH-iniidazole 2-(1H-imidazoI-4(5)yhnethyl)74-methyl-3,4dihydro-2H-naphthalen-I -one 6-(1H-imidazol-4(5)yhnethylene)-6,7,8,9- WO 02/076950 WO 0/07950PCT/UJS02/08222 E-xample Stutr/ o p u d Brmonidme Oxymeazoline Brimonidine StrctreCopond Alpha 2A Alpha 2B Alpha 2C B-6 HCI 0 0.35 0

S

4(5)-thiochrom-3-ylmethyIlHimidazole, hydrogen chloride salt N S0 0.5 0.2

HN

0 3.-(lJ-iniidazol-4(5)ylmethyl)thiochroman-4-one H N ,S0 0.5 0.37 0.

3-(1H-imidazol-4(5)ylmethylene)thiochroman-4one B-7a -0 0.3 0

HN

0 2-(IH-iniidazol-4(5)yhmethylene)indan-I -one B-Ila N 0.4 0.9 0

H

WO 02/076950 WO 0/07950PCT/UJS02/08222 Exam~e Sructre/Cmpoud BrmoniineOxymetazoline Brimonidine Exam le trutureCom oun Alpha 2A Alpha 2B Alp a2 4(5)-(6,7,8,9-tetrahydro-5Hbenzocyclohepten-6-ylmethyl)- IH-imidazole B-ThHt 0 0.3 0 0 2-(1H-imiddazol-4(5)yhnethyl)indan-1 -one B-1 HOI 0.15 0.45 0.3 4(5)-(7-mnethoxy-1 ,2,3,4tetrahydronaphthalen-2ylmethyl)-lH-inlidazole, hydrogen chloride salt B-la 0.15 0.6 0 H N 0 0 2-(1H-imidazol-4(5)ylmethyl)-7-rnethoxy-3,4: dihydro-2H-naphthalen- 1 -one B-9b HCI 0 0.68 0.15 N

S

0 5-(1H-iinidazol-4(5)yhnethyl)-6,7-dihydro-5H- WO 02/076950 WO 02/76950PCT/US02/08222 Example Structure/Compound Brimonidine Oxynietazoline IDrinionidiue I Alpha 2A Alpha 2B Alpha 2C hydrogen chloride salt B-7c N0 0.9 0 4(5)-indan-2-ybmethyl-11Hiniidazole 0 0.3 0 'HN K 4(5)-(4,4-dimethyl,2,3,4ylrnethyl)-IH-iniidazole B-8b HCI 0 0.6 0.2 pN

HN

4(5)-(7-inethyl,2,3,4tet-ahydronaphthalen-2ylmethyl)-111-imidazole, hydrogen chloride salt IB-8a.p 0 0.4 0

HN

0 2-(1H-imidazol-4(5)yhnethyl)-7-methyl-3,4dihydro-2H-naphthalen-l -one WO 02/076950 WO 02/76950PCT/US02/08222 Ea le Structure/Compound Brimnidine OxYmetazOline Brimonidine, Alpha 2A Alpha 2B Alpha 2C K-1 HtN 0 0.53 0 tetrahydrobenzo[b]thiophen-2ylmethyl)-1Iimidazole C-12 Br NH 0.2 1.3 0.3 s N, 4(5)-(4-bromothiophen-2ylmethyl)-IHi-imidazole C-13 Ph NH0 0.5 0 4(5)-(4-.phenylthiophen-2ylmethyl)-1Hi-imidazole K-3 0 0.37 0 H N 'S S 4(5)-(5,6-dihydro-4J1thieno[2,3-b]thiopyran-2ylnethyl)-lH-imidazole K-2 NH 0 0.7 0 0 N 4(5)-(5-tert-butylfuran-2ylniethyl)-JH-inmidazole WO 02/076950 WO 02/76950PCT/US02/08222 *Example Structure/Conipoun d Brinionlidine Oxymetazolinet Brimonidine Alpha 2A Alpha 2B Alpha 2C C-11 NH 0.2 0.5 0 0 N 4(5)-(5-ethylfaran-2-ybnethyl)lH-imidazole C-14 0.27 0.7 0.3 HCa H/ S 4(5)-(4-methyltbiophen-2yhnethyl)-lH-inmidazole, hydrochloride salt N-i 0.24 0.75 0.26 HCI 0 2-(1H-iniidazol-4(5)ylmethyl)-3,4,5,6,7,8hexahydro-2H-naphthalen-l one, hydrochloride salt Q- N 0.1 0.9 0.23 0 6-(lH-iinidazol-4(5)ylmethyl)-7,8-dihydro-6H- WO 02/076950 WO 02/76950PCT/US02/08222 ~Examnple Struci ture/Compound Brimouidint Oxymetazoline Brinonidine Alpha 2A IAlpha 2B I Alpha 2CI (IE)-6-(1H-imidazol-4(5)ylmethylene)-7,8-dihydro-6H- (Z)-6-(lH-irnidazol-4(5)yhnethylene)-7,8-dihydro- 6

H-

N0 0.5 0.05 4(5)-(2,3,4,4a,5,6,7, 8 octahydronaphthalcfl-2ylmethyl)-1Hi-imidazole HN/- NIN 0.1 0.8 0.1 2 HCI 6-(1H-ilnidazol-4(5)y1miethyl)-5,6,7,8-tetrahydroquinolinae, dihydrochloride WO 02/076950 WO 02/76950PCT/US02/08222 Example Structure/Compound Brimonidine Oxyinetazoline Brimonidine Alpha 2A Alpha 2B Alpha 2C 0 0 0.67 0.1

N

NJ HCI

H

pentalen-2ylmethyl-11{-imidazole, hydrochloride B-9c N 0 0.3 0

NS

H

HCI

IH-imidazole, hydrochloride H- PN 0 0.6 0.4 (041-40415.

6-(1I{-imidazol4(5)ylniethyD)-5,6,7,8-tetrahydroisoquinoline, fumarate R-2 HN 0 0.6 0.4 2 HC1 0 6-(lH-imidazol-4(5)ylmethyl)- 7,8-dihydro-6Hdihydrochioride WO 02/076950 WO 02/76950PCT/US02/08222 Example Structure/Compound Brmndn OyAzl Brilpho2idn R-1 H 0.3 0.8 0.4

NN

N N 0 (E)-6-(IH-iinidazol-4(5)yhmethylene)- 7,8-dihydro-6H- P-1 /HN4 1 0 0.4 0

_HN

0

(C

4

H

4 0 4 1 7-(11{-iinidazol-4(5)ylmcthyl)- 6,7-dihydro-5Hisoquinolin-8-one, fttmarate P-2 N. 0 0.4 0 HN N

(C

4

H

4 0 4 )1.

7-(lH-iimidazol-4(5)yhnethyl)- 5,6,7,8-tetrabydroisoquinolmne, fumarate N-3 Hk N0 0.75 0

C

4

H

4 0 4 ,4,5,6,7,8octahydronaphthalen-2ylrnethyl)-1H-imnidazole, fwnarate WO 02/076950 WO 02/76950PCT/US02/08222 Example Structure/Compound Brimonidine Oxynetazollne Brimonidine t Alpha 2A I Alpha 2B Alpha 2C 0 1.0 0 0.

6-(1H-in-idazol-4(5)-ylone WO 02/076950 WO 02/76950PCT/US02/08222 [Example Structure/Compound BiodneOxYxntaoline Brinouidine Alpha 2A Alpha 2B IAlpha 2C S C 4

H

4 0 4 0 .6 0

H

N

<\I

4(5)-(4a-methyl- 2,3,4,4a,5,6,7,8-octahydronaphthalen-2-ylmethyl)- 11imnidazole, but-2-enedioic acid salt T-1 C 4

H

4 0 4 0.25 0.8 0.35

H

N

4(5)-(3-niethyl-cyclohex-2enyhnethyl)-1II-imidazole,but-2-enedioic acid salt T-2 H 0 0.7 0

N

<\I

N

C

4

H

4 0 4 4(5)-(3,:5,5-trimethyl-cycloliex- 2-enylinethyl)-lH-imidazole, but-2-enedioic acid salt T-3 H 0 1.08 0.36

N

C

4

H

4 0 4 4(5)-(3-methvl cvclgoent-2enyllmEthyl)-lHI-imidazole.

but-2-enedioic acid WO 02/076950 WO 02/76950PCT/US02/08222 Examnple I Structure/ConiPouJad Brimnouidine Oxyrnetazoline Brimonidine Alpha 2A IAlpba 2B IAlpha 2C uiH 0.17 0.6 0.43

N:

ILo

N

C

4

H

4 0 4 4(5)-cyclohex-2-enyhnethyl- 1fl-imidazole, but-2-enedioic acid salt U-2 H 0.2 0.6 0.3 Na

N

C

4

H

4 0 4 4(5)-(4-niethyl-cyclohex-2enyhnethyl)-IH-iinidazole, but-2-enedioic acid salt V0 0 0.4

N

N

H C 4

H

4 0 4 2-(1 ylnietbyl)-cyclohexanofle, but- 2-enedioic acid salt -1N 0.07 0.55 0.07 H

C

4

H

4 0 4 4(5)-(3,4-Dimethyl-cyelohex- 3-enylnlethyl)-lH-imiTdazolc, but-2-enedioic acid salt WO 02/076950 WO 02/76950PCT/US02/08222 Exampledin OxylnetaCmpoinzoline lBrimunidiue Examle Srucure/ompund lph 2A lph 2B3 Alpha 2C W-2 N0 0.6 0.7

N

H C 4

H

4 0 4 4(5)-Cyclohex-3-enylmethyl- I H-iniidazole, but-2-enedi oic acid salt X-1 N 0.15 0.8 0.11

N

H

C

4

H

4 0 4 4(5)-(4-Methyl-cyclohex-3enylmethyl)-1H-imidazole, but-2-enedioic acid salt X-2 <N 0 0.56 0

N

H

C

4

H

4 0 4 4(5)-(4-Ethyl-cyclohex-3enyhnethyl)- il-imiidazole, but-2-enedioic acid salt X-3 N 0.19 08 K 0.8 0 N H

C

4

H

4 0 4 4(5)-(4-Pentyl-cyclohex-3enylmethyl)- 11{imidazole, but-2-enedioic acid salt WO 02/076950 WO 02/76950PCT/US02/08222 I

I

Example Structure/Compound B3ri nonidine IOxymetazoline Alpha 2A IAlpba 2B Brimonidine Alp~ha 2C xymtaolne0.63 1.0 0.58 clonidine 0.78 0.75 0.55 .0.93 4(5)-(3-methyl-thiophen-2- 0.31.4 hethyl)-1Himidazole 1-A <N 0 0.7 0 H

C

4

H

4 0 4 -BH 0 0.7 0

I-BKN

<N

C

4

HR

4 0 4

N

0 U.0

IC

4

H

4 0 4 I WO 02/076950 wO 02/76950PCT/US02/08222

NN

Nr

H

WO 02/076950 WO 02/76950PCT/US02/08222 Example Structure/Compound Brimoitidine Oxynletazoline Brinionidine Alpha2A Alpha2B_ Alpha2C 1N 0 0.7 ND Nr 0 0.8

N:I

IP N 0 0.7 0.3

N

H

IQ N 0 0.75 0

N

H

Example Z lOP-Lowering and Sedative Side Effects Measurements of lOP were made in fully conscious female cynomolgus monkeys weighing 3-4 kg with sustained elevated lOP that was produced in the right eye by argon laser photocoagulation of the trabecular meshwork. Animals were usable for experiments 2 months following surgery. During the experiments, monkeys sat in specially designed chairs (Primate Products, San Francisco), and were fed orange juice and fruit as needed. A 30R model Digilab pneumnatonometer (Alcon, Texas) was used to measure Twenty five gl of an anesthetic (proparacaine) was topically applied to each monkey before lOP measurements to minimize ocular WO 02/076950 PCT/US02/08222 110 discomfort due to tonometry. Two baseline measurements were made prior to instillation of the drugs, followed by periodic measurements up to 6 hours post-instillation. The test compounds were administered unilaterally as-a single 50 jl eye drop; the contralateral eyes received an equal volume of saline.

Many of the a2B or c2B/2C selective compounds of the examples were tested in the monkeys. Surprisingly, as Table 2 shows, these structurally diverse compounds all lowered IOP in the treated eye.

At the same time, sedation was measured and assessed according to the following score: 0 alert, typical vocalization, movement, etc.; 1 calm, less movement; 2= slightly sedated, some vocalization, responsive to stimulation; 3 sedated, no vocalization, some response to stimulation; 4 asleep.

The compounds of the present invention also did not cause sedation. This contrasts with the action of clonidine and brimonidine, which caused sedation.

Table 2. The effects of a 2 -adrenoceptor agonists on IOP and sedation in conscious cynomolgus monkeys following ocular administration in eyes made unilaterally hypertensive by argon laser photocoagulation. Measurements were made periodically up to 6 hours. Sedation was assessed subjectively during the IOP experiments using the following scoring: 0 alert, typical vocalization, movement, etc.; 1 calm, less movement; 2 slightly sedated, some vocalization, responsive to stimulation; 3 sedated, no vocalization, some response to stimulation; 4 asleep. Number of animals per group WO 02/076950 WO 02/76950PCT/US02/08222 Maximum Decrease From Table 2 Compounds Dose(% Saline Clonidine 0.1 0.3 Brimonidine 0.1 0.3 J-1 1 3 E-1 0.3 1 c-i 1 3 D-11 M1 C-21 Pretreatment Levels Hypertensive Eye 25 4 411±5 25:L 3 40±1:4 26 5 33 ±3 25:±4 27 ±3 25:E4 29± 4 25.6 3.9 22.5 4:5.4 29.6 5.5 Sedation (0-4) 0-1 1 2 1 2 0 0 0 0 0 0 0 0 0 WO 02/076950 WO 02/76950PCT/US02/08222 C-8 B-3b 0.3 1 0.3 0.1I 0.3 0.3 1 1 0.03 0.3 0.03 0.3 0.1 0.3 1 13.7 25.1 4.9 20.6:1:4.8 25.0 6.4 31.2 ±3.3 25.9 31.2 4.3 17.7 29.3 ±4.9 32.3 ±5.7 12.4± 3.7 27.3 3.1 16.4 ±4.7 26.5 ±3.8 22.0±=L4.6 17.0 4.2 18.1 ±5.2 0 C-7 0 B-2d WO 02/076950 PCT/US02/08222 B-9a 0.03 17.6 1.7 0 0.1 26.7 6.1 0 0.3 24.8 ±3.3 0 1 26.8 5.4 0 B-6 0.3 13.8 2.4 0 1 22.1 6.3 0 B-9b 0.1 18.7 5.5 0 0.3 26.9 6.1 0 Example AA Measurement of Cardiovascular Side Effects Cardiovascular measurements were made in a different group of monkeys using a BP 100S automated sphygmomanometer (Nippon Colin,. Japan). Intravenous (IV) administration of certain of the compounds of the present invention at doses ten to thirty times higher than the doses for clonidine and brimonidine did not reduce heart rate or lower blood pressure. Interestingly, the compound 4(5)-3methylthiophen-2-ylmethyl)-1H-imidazole, which has intrinsic activity of 0.43 at the a2A-subtype, exhibited a weak effect on heart rate.

Clonidine and brimonidine had even greater effects on heart rate. See Table 3 below.

Table 3. The effects of c 2 -adrenoceptor agonists on cardiovascular variables in conscious cynomolgus monkeys following i.v. administration.

WO 02/076950 WO 02/76950PCT/US02/08222 114 Measurements were made periodically up to 6 hours. Number of animals per group (6-10).

[Table 31 Maximum Decrease From Pretreatment Levels Mean Arterial Blood Heart Rate Pressure Compounds Dose (ug/kg) 8 -±3 Saline 7+4 7 4 Clonidine 17 2917 32 ±4 35+±5 50 Brimonidine 17 3613 52+3 37 ±5 54 1 J-1 17 7+±5.3 13 ±4 4 +2 6+2 167 7+ 5 3+3 500 1313 7+4 E-1 17 7±4 11+4 7+2 14+5 167 9+4 11+5 c-1 50 12.8+=:12 12+4 M 500 0.8 5.5+ 1.9 C-2 500 6.6+ 1.7 6.5+2.9 C-9 3.0 5.0+±2.3 9.4± 4.1 0.1+ 3.8 1.8* 16+L 3.2 500 6.0+±2.2 59± 3 C-3 500 2.3 ±2.7 10.6 3.4 500 3.9+±2.8 7.1+=L3.9 B-3b, 50 2.4 ±4.3 10 0.0+2.8 WO 02/076950 PCT/US02/08222 C-4 500 C-7 500 J-2 500 J-3 500 B-2b 500 B-2d 500 B-9a 500 B-9b 500 50 methylthiophen 167 -2-ylmethyl)- 1H-imidazole showed increase from base levels 5.3 2.9 3.0 3.9 +0.6 3.1* +1.0 ±2.1* 5.7 1.4 +8.9 3.4* +10.8 3.2* 2.8 1.8 9±3 8±6 10.9 3.6 6.1 3.7 6.4 3.3 +10.6 6.4 3.6 +15.5 3.4* +23.8 4.4* +20.2 3.4* 23 4 32 8 EXAMPLE BB The studies in the above Examples Z and AA demonstrate that a therapeutic effect of alpha2 agonists can be separated from sedative and cardiovascular side effects. This separation is accomplished with compounds that share the property of being preferentially active at the alpha2B and alpha2B/alpha2C subtypes relative to the alpha2A subtype.

The prior art alpha2 adrenergic agonists, which activate all three alpha2 receptors, cause sedation, hypotension and bradycardia, preventing or severely limiting their use for treating diseases and disorders that are known to be ameliorated by them. Such diseases and disorders include muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases including optic neuropathy, spinal ischemia and stroke, memory and cognition deficits, attention deficit disorder, psychoses including manic disorders, anxiety, depression, hypertension, WO 02/076950 PCT/US02/08222 116 congestive heart failure, cardiac ischemia and nasal congestion. See, for example, Hieble et al., "Therapeutic applications of agents interacting with alpha-adrenoceptors, in Alpha-adrenoceptors: molecular biology, biochemistry and pharmacology". Prog. Basic Clin. Pharmacol. (Basel, Karger) 8, pp. 180-220(1991). For example, clonidine has been shown to be clinically effective in providing pain relief for postoperative, cancerassociated and neurogenic pain. But, as stated in Maze and Tranquilli, Maze MB and Tranquilli, W. "Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia". Anesthesiology 74, 581-605 (1991), the "full clinical promise" of this and other alpha2 agonists requires the development of compounds that do not cause sedation, hypotension and bradycardia.

The above-listed diseases and disorders are treatable by activation of a2B or a2B/2C receptor subtype(s). Therefore, the alpha2 compounds described above that have been shown above not to elicit sedation and cardiovascular effects, are useful and advantageous in the treatment of these conditions.

Amelioration of neuronal degeneration in glaucomatous neuropathy is another example of the novel utility of the compounds of the invention.

Recent studies have demonstrated that clonidine and other alpha2 agonists are neuroprotective of retinal cells in several rat models of neuronal degeneration. These models include light-induced photoreceptor degeneration in albino rat, as described in Wen et al, "Alpha2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage." J. Neurosci. 16, 5986-5992 and calibrated rat optic nerve injury resulting in secondary loss of retinal ganglion cells, as described in Yoles et al, "Injury-induced secondary degeneration of rat optic nerve can be attenuated by alpha2-adrenoceptor agonists AGN 191103 and brimonidine". Invest. Ophthalmol. Vis. Sci. 37, WO 02/076950 PCT/US02/08222 117 540,S114. However, unlike the compounds of the present invention, the doses used in these studies 0.1 to >1 mg/kg by intraperitoneal or intramuscular injection-- also cause sedation and cardiovascular effects.

Induction of the expression of basic fibroblast growth factor (bFGF) is considered a sensitive indicator of alpha2 receptor activation in the retina (Wen et al above) and measurement of bFGF induction following topical administration of alpha2 agonists to rat eyes indicates that approximately a 1% dose is necessary to induce a 2-3 fold increase in bFGF levels that correspond with alpha2 agonist mediated neuroprotection (See Wen et al, above, and Lai et al, "Neuroprotective effect of ocular hypotensive agent brimonidine", in Proceedings of XIth Congress of the European Society of Ophthalmology (Bologna, Monduzzi Editore), 439-444.) These topical doses of current alpha2 agonists such as clonidine are known to result in systemic side effects such as sedation and hypotension that would prevent their use as ocular neuroprotective agents. Additionally commonly assigned and copending application, 08/496,292 filed on 28 June, 1995, discloses and claims the use of certain non-selective a2-adrenergic agents in treating neural injury, the contents of which are hereby incorporated by reference in their entirety.

The compounds of the present invention do not cause sedation and cardiovascular effects following topical administration of doses of at least 3% in monkeys. Thus, neuroprotective concentrations of these compounds can be reached in humans without causing side effects. In fact, as reported below, the compound of Example B-9(b) has been shown to be neuroprotective in the calibrated rat optic nerve injury model of Yoles et al, above. See Table 4, below.

Table 4: Retinal Ganglion Cell Numbers at 2 Weeks Post-Injury (cells/microscopic field) WO 02/076950 PCT/US02/08222 118 Control Example B-9(b) (vehicle (0.5 mg/kg i.p.) 33 8 73 12 n=8 This level of neuroprotection is comparable to the effect seen in previous studies with the standard alpha 2-adrenoceptor agonist, brimonidine, and the neuroprotective agent, MK801.

Example CC Alleviation of pain including neuropathic pain is another example of a disorder in which the compounds of the invention are useful and advantageous since pain is alleviated without undesirable side effects.

Clonidine, an agonist that activates all three alpha2 receptors, has been used clinically for treating chronic pain, but its utility for this indication is limited because it causes sedation and cardiovascular side effects.

Compounds of the present invention were compared to clonidine and brimonidine in a rodent model of neuropathic pain that is known to be predictive of clinical activity. (See, for example, Kim, S. and Chung, J.

"An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat." Pain 50 pp. 355-363 (1992).) Following ligation of two spinal nerves, the animals develop a sensitivity to normally non-painful stimuli such as touch. The ability of alpha2 compounds to reverse this sensitivity, called allodynia, was tested 30 minutes after dosing by either intrathecal or intraperitoneal administration. The sedative activity of each compound was also measured using an activity chamber.

WO 02/076950 WO 02/76950PCT/US02/08222 119 The compounds of the invention, exemplified by N-i, are able to alleviate the allodynia without causing sedation, even at very high doses. This is in contrast to clonidine and brimonidine, which cause sedation at doses only slightly higher than their anti-allodynic doses. See tables 5 and 6, below.

Table 5. The anti-allodynic and sedative effects of alpha2-adrenoceptor agoriists in rats 30 minutes following intrat-hecal administration Comound Dose (jig) Reversal of Tacile Sedation on) Allodynia on) alondine 0.1 20* N 1 96* ND N-i 3 13 ND 64* 0 300 ND 0 p<0.05 compared to saline control 9ND signifies no data Table 6. The anti-allodynic and sedative effects of alpha2-adrenoceptor agonists in rats 30 minutes following intraperitoneal administration Compound Dose Reversal of Tactile Sedation(% (img/sg) Allodynia(% rimondine 3 0 ND 37* 24 300 ND 67* (Table 6 cont) Dose Reversal of Tactile Sedation Cor oud L~L Allodna 'a P:\WPDOCS\HjuSpccs 2\78269053 pgs doc-14/042008 00 -120- N-1 3 3 ND 41* ND 10,000 ND 0 p 0.05 compared to saline control ND signifies no data The results of these Examples demonstrate that the common side effects of c2adrenoceptor drugs are mediated by the o2A-subtype and that their ocular antihypertensive and other therapeutic actions can be mediated by a subtype other than the c2A-subtype.

Thus,.c2-adrenoceptor compounds of unrelated structural classes, that have in common low functional activity at the o2A-subtype, lower IOP and elicit other therapeutic actions without dose-limiting side effects.

While particular embodiments of the invention have been described, it will be understood, of course, that the invention is not limited thereto since many obvious modifications can be made, and it is intended to include within this invention any such modification as will fall within the scope of the appended claims.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Having now described the invention, we claim:

Claims (3)

1. A process for the treatment of chronic pain comprising administering to l t a mammal suffering from chronic pain a pharmaceutical composition Scomprising a therapeutically effective dose of a selective agonist of the o2B adrenoceptor subtype or o2B/o2C adrenoceptor subtype(s), said selective Sagonist having a structure selected from compounds having the formula 3 (R x (R2 R N R (Rx H I wherein the dotted lines represent optional double bonds; R is H or lower alkyl; X is S or wherein R' is H or lower alkyl or R' is absent when X is S or when the bond between X and the ring represented by Y is a double bond; Y is O, N, S, (CR 1 x)y, wherein y is an integer of from 1 to 3, -CH CH- or -Y'CH 2 wherein Y' is O, N or S; x is an integer of 1 or 2, wherein x is 1 when R 2 R 3 or R 4 is bound to an unsaturated carbon atom and x is 2 when R 2 R 3 or R 4 is bonded to a saturated carbon atom; R 2 is H, lower alkyl, halogen, hydroxy or lower alkoxy, or oxo; R 3 and R 4 are, each, H, lower alkyl, hydroxy, lower alkoxy, or phenyl or, together, are -Y'(C(R 2 2 (C(R 2 -(C(R 2 and 2 wherein z is an integer of from 3 to 5, z' is an integer of from 2 to 4 and x and y are as defined above, and further either end of each of these divalent moieties optionally attach at either R 3 or R 4 to form the condensed ring structure P \WPDOCS\HjwSpccs 2k78269053 pgs dcI4/0421009 00 0 122- (2 (R2)x R R R \D Y t and the ring thus formed is totally unsaturated, partially unsaturated, or N totally saturated provided that a ring carbon has no more than 4 valences, 0nitrogen no more than three and 0 and S have no more than two; or W V wherein W is a bicyclic radical selected from the group consisting of R RR wherein R 5 R 6 R 7 and R 8 are selected from the group consisting of H and lower alkyl provided that at least one of R 5 and R 6 or R 6 and R 7 are OC(R')C(R 9 to form a condensed ring with wherein R 9 is H, lower alkyl or oxo and R 10 wherein R 10 is H, lower alkyl, phenyl or lower alkyl substituted phenyl, and Z is O or NH. 01-05-'08 12:42 FROM-DCC SYDNEY +61292621080 T-469 P09/013 F-422 P\WPDOCMwSpcc 2\76905 p .do-IfOOM2 00 0

123- 2. A process for treating elevated intraocular pressure in a mammal, comprising administering to said mammal a pharmaceutical composition O containing a therapeutically effective dose-of selective agonist of an o2B adrenoceptor subtype or a2B/oe2C adrenoceptor subtype(s), said selective \O agonist having a structure selected from the compounds as defined in claim 1. n 3. A process of claim 1 or 2, wherein the agonist has an efficacy at least c about 0.3 greater at the c2B or a2C adrenoceptor subtypes than at the o2A 0 adrenoceptor subtype, and wherein its efficacy at the c2A adrenoceptor subtype is -0.4. 4. A process of any one of claims 1 to 3, wherein the agonist is at least ten times more potent at the a2B or o2C adrenoceptor subtype than at the a2A adrenoceptor receptor. A process of claim 4, wherein the active compound is at least one hundred times more potent at the c2B or c2C adrenoceptor subtype than at the o2A adrenoceptor subtype. 6. A process of any one of claims 1 to 3, wherein said agonist has no detectable activity at the a2A adrenoreceptor subtypes. 7. A process of any one of claims 1 to 3, wherein said agonist has no detectable activity at the a2A and o2C adrenoreceptor subtypes. 8. A process of any one of claims 1 to 5, wherein approximately 0.001% to by weight of the agonist is administered topically to the mammal in daily or twice daily doses. COMS ID No: ARCS-188850 Received by IP Australia: Time 12:42 Date 2008-05-01 P:\WPDOCS\Hjw\Spcs 2\78269053 pgs doc.-1/042008 00 O -124- 9. A process of claim 8, wherein approximately 0.01% to 3.0% by weight Sof the agonist is administered topically to the mammal in daily or twice daily doses. 10. A process for administering to a mammal a pharmaceutical composition t comprising a therapeutically effective dose of a compound to treat or prevent a C pathological condition selected from the group consisting of muscle spasticity; Spain; neurodegenerative diseases, spinal ischemia and stroke; memory and cognition deficits; psychoses, anxiety and depression; hypertension; congestive heart failure; cardiac ischemia and nasal congestion, wherein said compound has adrenergic activity and is a selective agonist of the o2B or c2B/c2C adrenoceptor receptor subtype(s), said selective agonist having a structure selected from the compounds as defined in claim 1. 11. A process for administering to a host mammal a pharmaceutical composition containing an effective dose of an active compound having adrenergic activity, said active compound having a structure selected from the group consisting of the compounds as defined in claim 1 to treat muscle spasticity, pain, neurodegenerative diseases, spinal ischemia and stroke, memory and cognition deficits, attention deficit disorder, psychoses, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia or nasal congestion wherein the active compound has the biological property that the compound is a selective agonist of c2B or a2B/c2C receptor subtype(s), said selectivity being measured in an assay using cells that naturally express the individual c2 subtypes or have had one of the subtypes introduced, the receptors being human or from a species that has been shown to have a similar pharmacology, in which assay the efficacy relative to brimonidine of the active compound at the o2B or the o2C receptor subtype is measured to be at least 0.3 greater than the efficacy relative to brimonidine of the active compound at the o2A receptor subtype and its efficacy at the c2A receptor is and/or the active compound is at least approximately 10 times more potent at the c2B or o2C receptor subtypes than at the o2A receptor subtype. P \WPDOCS\Hj\Sp s 2\78269053 pgs do. 14/04I2008 00 O -125- J 12. The process of claim 11 wherein the selectivity of said selective agonist is measured in an RSAT assay in which activation of the o2A and c2C receptor ~t subtype by the test compound is compared to brimonidine and the a2B receptor C subtype is compared to oxymetazoline and wherein the respective o2A, o2B and o2C receptor subtypes are expressed in NIH-3T3 cells, and in which assay the efficacy relative to brimonidine of the active compound at the a2C receptor subtype or the efficacy relative to oxymetazoline of the active compound at the a2B receptor subtype is measured to be at least 0.3 greater than the efficacy relative to brimonidine of the active compound at the d2A receptor subtype, and its efficacy at the o2A receptor subtype is 50.4 and/or the active compound is at least approximately 10 times more potent at the o2B or o2C receptor subtypes than at the c2A receptor subtype. 13. Use of a compound as defined in claim 1 in the manufacture of a medicament as a selective agonist of the o2B adrenoceptor subtype or o2B/o2C adrenoceptor subtype(s). 14. Use of a compound as defined in claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a condition selected from muscle spasticity; pain including chronic pain; neurodegenerative diseases, spinal ischemia and stroke; memory and cognition deficits; psychoses, anxiety and depression; hypertension; congestive heart failure; cardiac ischemia, nasal congestion and elevated intraocular pressure. A compound selected from the group consisting of: P %WPDOCSljw\Ss 2\78269)53 pgsdocI4'0412008 00 O -126- (R (R6)P H2 (R)p H 2 (R 6 )p C and p(R 6 x(RI) H2 (R 6 )p (R 6 )p wherein RI is independently selected from the group consisting of H; halogen; CI-4 alkyl; C-4 alkenyl; CI- 4 alkynyl; -COR 4 where R4 is H, Ci- 4 alkyl or C-4 alkoxy; C3-6 cycloalkyl; aryl; cyano; nitro; trihalomethyl; oxo; or (CH 2 )n-X-(CH 2 )m-(R 5 where X is O, S or N, n is 0-3, m is 0-3, o is 0-1, and R 5 is methyl or Hi-2, each R 6 is independent selected from the group consisting of H; halogen; C-4 alkyl; CI- 4 alkenyl; CI- 4 alkynyl; -COR 4 where R 4 is H, C 1 4 alkyl or C14 alkoxy; C3- 6 cycloalkyl; aryl; cyano; nitro; trihalomethyl and oxo wherein each p is independently 1 or 2 and Y is (C(R 7 )z) 2 wherein R 7 is independently defined identically to RI and z is independently 1 or 2, said compound further having selective agonist activity at the o2B or o2B/o2C adrenergic receptor subtype(s) over the o2A adrenergic receptor subtype, and all pharmacologically acceptable salts, esters, stereoisomers and racemic mixtures thereof. 16. A compound of claim 15, wherein Y is CH2-CH2. 17. A compound of claim 15 or claim 16, wherein RI, R 6 and R 7 are independently H; halogen; C 14 alkyl; C 1 -4 alkenyl; or C-4 alkynyl. 01-05-'08 12:42 FROM-DCC SYDNEY +61292621080 T-469 P010/013 F-422 P:.WvPOC iUjhASpa 7 2\296SI 2p,.daol052008I 00 0

127- 18. A compound of any one of claims 15 to 17, wherein R1 is H and x is 2. 19. A compound of any one of claims 15 to 18, wherein at least one R6 is H. \I 20. A compound of claim 19, wherein at least two R 6 are H. ci 21. A compound of claim 20, wherein at least three RS are H. 0 o 22. A compound of claim 21, wherein at least six R 6 are H. 23. A compound of claim 22, wherein eight Re are H. 24. 4(5)-(1,2,3,4,5,6,7,8-Octahydronaphthalen-2-ylmethyl)- 1H-imidazole prepared by the method according to Example N as hereinbefore described. 4(5)-(3,4-Dimethyl-cyclohex-3-enylmethyl)- 1H-imidazole, but-2- enedioic acid salt prepared by the method according to Example W-1 as hereinbefore described. COMS ID No: ARCS-188850 Received by IP Australia: Time 12:42 Date 2008-05-01